KR20220017946A - Anti-B7-H4 antibody-drug conjugates and medical uses thereof - Google Patents
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Abstract
항-B7-H4 항체-약물 접합체 및 이의 의학적 용도를 제공한다. 구체적으로, 항-B7-H4 항체 또는 이의 항원-결합 단편, 상기 항-B7-H4 항체의 CDR 영역을 포함하는 인간화된 항체, 및 이의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매 화합물, 및 상기 항체-약물 접합체 또는 약학적으로 허용가능한 염 또는 이의 용매 화합물의 약학 조성물, 및 항암 약물로서 이의 용도, 특히 B7-H4의 고 발현을 갖는 질병 또는 장애의 치료를 위한 약물의 제조에서의 용도를 제공한다.Anti-B7-H4 antibody-drug conjugates and medical uses thereof are provided. Specifically, an anti-B7-H4 antibody or antigen-binding fragment thereof, a humanized antibody comprising the CDR regions of the anti-B7-H4 antibody, and an antibody-drug conjugate thereof or a pharmaceutically acceptable salt or solvate thereof , and pharmaceutical compositions of said antibody-drug conjugates or pharmaceutically acceptable salts or solvates thereof, and their use as anticancer drugs, in particular in the manufacture of drugs for the treatment of diseases or disorders having high expression of B7-H4 provide use.
Description
본 발명은 생물의학 분야에 관한 것이다. 구체적으로, 본 발명은 항-B7-H4 항체-약물 접합체 및 이의 의학적 용도에 관한 것이다.The present invention relates to the field of biomedical science. Specifically, the present invention relates to anti-B7-H4 antibody-drug conjugates and medical uses thereof.
종양 면역요법은 종양 요법 분야에서 장기간 지속 가능한 연구 개발 핫스팟(hotspot)이고 T 세포 종양 면역요법이 그 핵심 위치에 있다. 종양 회피는 종양 면역요법의 큰 장애물이다. 대부분의 종양은 다양한 정도로 숙주 면역계에 의해 인식될 수 있는 항원을 발현한다. 그러나 많은 경우 효과기 T 세포의 비효율적인 활성화는 불충분한 면역 반응을 일으키고, 따라서 종양 세포는 면역계에 대한 이의 억제 효과에 의해 종양 성장을 촉진한다. 종양 면역요법은 종양을 죽이기 위해 종양이 있는 환자의 킬러 T 세포 및/또는 기타 면역 세포를 최대한 활용하고 동원하는 것이다.Tumor immunotherapy is a long-term sustainable research and development hotspot in the field of oncology, and T-cell tumor immunotherapy is at its core. Tumor avoidance is a major hurdle for tumor immunotherapy. Most tumors express antigens that can be recognized by the host immune system to varying degrees. However, in many cases inefficient activation of effector T cells results in an insufficient immune response, and thus tumor cells promote tumor growth by virtue of their inhibitory effect on the immune system. Tumor immunotherapy is the maximization and recruitment of killer T cells and/or other immune cells from a patient with a tumor to kill the tumor.
CD28 수용체 및 이의 리간드에 대한 연구는 B7 슈퍼패밀리라고 하는 분자의 특성화로 이어졌다. B7 패밀리의 구성원은 면역글로불린-유사 V 도메인(IgV) 및 면역글로불린-유사 C 도메인(IgC)을 갖는 면역글로불린의 한 부류이다. 그 구성원은 공동-자극 인자 B7.1(CD80) 및 B7.2(CD86), 유도성 공동-자극 인자 리간드(ICOS-L/B7-H2), 예정세포사-1 리간드(PD-L1/B7-H1), 예정세포사-2 리간드(PD-L2/B7-DC), B7-H3 및 B7-H4 등을 포함한다.Studies of the CD28 receptor and its ligands have led to the characterization of molecules called the B7 superfamily. Members of the B7 family are a class of immunoglobulins having an immunoglobulin-like V domain (IgV) and an immunoglobulin-like C domain (IgC). Its members are co-stimulatory factors B7.1 (CD80) and B7.2 (CD86), inducible co-stimulatory factor ligands (ICOS-L/B7-H2), programmed cell death-1 ligands (PD-L1/B7- H1), programmed cell death-2 ligand (PD-L2/B7-DC), B7-H3 and B7-H4, and the like.
인간 B7-H4는 282개 아미노산으로 이루어진 I형 막관통 단백질이다. 이의 암호화 유전자는 염색체 1의 p11.1 영역 중에 위치한다(문헌[Choi IH et al., J Immunol. 2003 Nov 1; 171(9): 4650-4]). B7-H4는 T 세포의 면역 반응에 대해 음의 조절 효과를 갖는다. B7-H4는 CD4+ 및 CD8+ T 세포의 분화 및 발생, 세포주기 진행 및 사이토카인 생산에서 광범위한 억제 역할을 한다(문헌[Sica GL et al., Immunity. 2003 Jun; 18(6): 849-61]). B7-H4 녹아웃 마우스에서 어떠한 면역세포 장애나 자가면역 현상도 발견되지 않았다(문헌[Zhu G et al., Blood. 2009 Feb 19; 113(8): 1759-67]; 문헌[Suh WK et al., Blood. Mol Cell Biol. 2006 Sep; 26(17): 6403-11]). 현재, B7-H4 및 이의 신호전달 경로의 수용체는 여전히 불명확하다.Human B7-H4 is a type I transmembrane protein of 282 amino acids. Its coding gene is located in the p11.1 region of chromosome 1 (Choi IH et al., J Immunol. 2003 Nov 1; 171(9): 4650-4). B7-H4 has a negative regulatory effect on the immune response of T cells. B7-H4 plays a broad inhibitory role in the differentiation and development of CD4+ and CD8+ T cells, cell cycle progression and cytokine production (Sica GL et al., Immunity. 2003 Jun; 18(6): 849-61). ). No immune cell dysfunction or autoimmune events were found in B7-H4 knockout mice (Zhu G et al., Blood. 2009 Feb 19; 113(8): 1759-67; Suh WK et al. , Blood. Mol Cell Biol. 2006 Sep; 26(17): 6403-11]). Currently, the receptors of B7-H4 and its signaling pathway are still unclear.
최근의 연구는 B7-H4 단백질이 다양한 종양 조직에서 풍부하게 발현되고, 이는 종양 세포가 신체의 면역계에 의한 공격을 피할 수 있게 함을 발견하였다. B7-H4 분자를 종양 요법의 표적으로서 고려하는 것은 종양 면역요법에 대한 신규의 방법을 제공한다.Recent studies have found that the B7-H4 protein is abundantly expressed in various tumor tissues, which enables tumor cells to evade attack by the body's immune system. Considering the B7-H4 molecule as a target for tumor therapy provides a novel approach to tumor immunotherapy.
현재, 인간 B7-H4는 유방암, 난소암, 폐암, 자궁경부암, 신장암, 방광암 및 간암과 같은 암 세포상에서 발현되는 것으로 공지되어 있다. B7-H4 mRNA의 발현은 비장, 폐, 흉선, 간, 골격근, 신장, 췌장, 고환 및 난소에서 발견된다. 단백질 수준에서, B7-H4 발현은 유방(유관 및 소엽), 나팔관 상피, 및 자궁내막선과 같은 조직에서 낮은 수준으로 발견된다. 관련된 연구는 또한 B7-H4가 종양-연관된 대식세포(TAM)에서 과발현되고(문헌[Kryczek, I. et al., J. Exp. Med. 2006, 203(4): 871-881]), 대식세포는 종양 미세환경의 중요한 성분을 구성하고 종양 질량의 50% 정도를 차지할 수 있음을 입증하였다.Currently, human B7-H4 is known to be expressed on cancer cells such as breast cancer, ovarian cancer, lung cancer, cervical cancer, kidney cancer, bladder cancer and liver cancer. Expression of B7-H4 mRNA is found in the spleen, lung, thymus, liver, skeletal muscle, kidney, pancreas, testis and ovary. At the protein level, B7-H4 expression is found at low levels in tissues such as the breast (ducts and lobules), fallopian tube epithelium, and endometrial glands. Related studies have also shown that B7-H4 is overexpressed in tumor-associated macrophages (TAM) (Kryczek, I. et al., J. Exp. Med. 2006, 203(4): 871-881), versus It has been demonstrated that phagocytes constitute an important component of the tumor microenvironment and can account for as much as 50% of the tumor mass.
암 치료를 위한 한 가지 전략은 항체를 담체로 사용하여 세포독성 분자를 암세포에 전달한 다음 해리된 소분자에 의해 암세포를 죽이는 것이다. 이 전략에 사용되는 약물을 항체-약물 접합체라고 한다. 애드세트리스(Adcetris)와 캐사일라(Kadcyla)는 현재 시판 중인 항체-약물 접합체이다. 현재, 많은 다국적 제약 회사는 종양에 대한 환자의 면역계 반응을 개선시키고 종양 세포를 직접 죽이는 목표를 달성하기 위해 B7-H4 및/또는 이의 약물 접합체에 대한 단클론 항체를 개발하고 있다. 관련 특허는 예를 들어 WO2013025779, US20140322129 등이다. 메드임뮨(Medimmune), 파이브프라임(FivePrime) 및 기타 회사의 항-B7-H4 단클론 항체는 현재 여전히 전임상 개발 단계에 있고; 제넨테크(Genentech)의 항-B7-H4 항체-약물 접합체 또한 전임상 개발 단계에 있다. One strategy for cancer treatment is to use antibodies as carriers to deliver cytotoxic molecules to cancer cells and then kill the cancer cells by dissociated small molecules. The drugs used in this strategy are called antibody-drug conjugates. ADCetris and Kadcyla are currently marketed antibody-drug conjugates. Currently, many multinational pharmaceutical companies are developing monoclonal antibodies against B7-H4 and/or its drug conjugates to improve the patient's immune system response to tumors and to achieve the goal of directly killing tumor cells. Relevant patents are, for example, WO20133025779, US20140322129 and the like. Anti-B7-H4 monoclonal antibodies from Medimmune, FivePrime and others are currently still in preclinical development; Genentech's anti-B7-H4 antibody-drug conjugate is also in preclinical development.
본 발명의 목적은 하기의 기술적 해법을 통해 성취되는 높은 친화성, 높은 선택성, 높은 식작용 효율, 높은 항암 활성, 높은 안정성, 높은 안전성 및 낮은 독성과 부작용을 갖는 항-B7-H4 항체-약물 접합체를 제공하는 것이다.An object of the present invention is to provide an anti-B7-H4 antibody-drug conjugate having high affinity, high selectivity, high phagocytosis efficiency, high anticancer activity, high stability, high safety, and low toxicity and side effects, which is achieved through the following technical solution will provide
하기 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:An antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof:
[화학식 A][Formula A]
상기 식에서,In the above formula,
D는 세포독성 약물이고;D is a cytotoxic drug;
L1 및 L2는 링커 단위(linker unit)이고;L 1 and L 2 are linker units;
y는 1 내지 20의 수이고;y is a number from 1 to 20;
Ab는 항체 경쇄 가변 영역 및 항체 중쇄 가변 영역을 포함하는 B7-H4 항체 또는 이의 항원-결합 단편이고;Ab is a B7-H4 antibody or antigen-binding fragment thereof comprising an antibody light chain variable region and an antibody heavy chain variable region;
상기 항체 중쇄 가변 영역은 서열번호 3, 서열번호 4, 서열번호 5, 서열번호 9, 서열번호 10 및 서열번호 11로 이루어진 군으로부터 선택된 서열에 제시된 하나 이상의 HCDR을 포함하고;wherein said antibody heavy chain variable region comprises one or more HCDRs set forth in a sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11;
상기 항체 경쇄 가변 영역은 서열번호 6, 서열번호 7, 서열번호 8, 서열번호 12, 서열번호 13 및 서열번호 14로 이루어진 군으로부터 선택된 서열에 제시된 하나 이상의 LCDR을 포함한다.The antibody light chain variable region comprises one or more LCDRs set forth in a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14.
본 발명의 하나의 실시태양에서, 상기 항체 중쇄 가변 영역은 또한 서열번호 3, 서열번호 4, 서열번호 5, 서열번호 9, 서열번호 10, 서열번호 11, 서열번호 23, 서열번호 24, 서열번호 25, 서열번호 29, 서열번호 30 및 서열번호 31로 이루어진 군으로부터 선택된 서열에 제시된 하나 이상의 HCDR을 포함할 수 있거나,In one embodiment of the present invention, the antibody heavy chain variable region also comprises SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 30 and SEQ ID NO: 31; or
상기 항체 중쇄 가변 영역은 또한 서열번호 43, 서열번호 44 및 서열번호 45로 이루어진 군으로부터 선택된 서열에 제시된 하나 이상의 HCDR을 포함할 수 있고;said antibody heavy chain variable region may also comprise one or more HCDRs set forth in a sequence selected from the group consisting of SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45;
상기 항체 경쇄 가변 영역은 서열번호 6, 서열번호 7, 서열번호 8, 서열번호 12, 서열번호 13, 서열번호 14, 서열번호 26, 서열번호 27, 서열번호 28, 서열번호 32, 서열번호 33 및 서열번호 34로 이루어진 군으로부터 선택된 서열에 제시된 하나 이상의 LCDR을 포함한다.The antibody light chain variable region comprises SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 33 and one or more LCDRs set forth in a sequence selected from the group consisting of SEQ ID NO:34.
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편은 항체 중쇄 가변 영역을 포함하고, 여기서 상기 항체 중쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the anti-B7-H4 antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region wherein the antibody heavy chain variable region comprises
서열번호 3에 제시된 HCDR1, 서열번호 4에 제시된 HCDR2 및 서열번호 5에 제시된 HCDR3; 또는HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 and HCDR3 shown in SEQ ID NO: 5; or
서열번호 9에 제시된 HCDR1, 서열번호 10에 제시된 HCDR2 및 서열번호 11에 제시된 HCDR3HCDR1 shown in SEQ ID NO: 9, HCDR2 shown in SEQ ID NO: 10 and HCDR3 shown in SEQ ID NO: 11
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편은 항체 중쇄 가변 영역을 포함하고, 여기서 상기 항체 중쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the anti-B7-H4 antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region wherein the antibody heavy chain variable region comprises
서열번호 23에 제시된 HCDR1, 서열번호 24에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 또는HCDR1 shown in SEQ ID NO:23, HCDR2 shown in SEQ ID NO:24 and HCDR3 shown in SEQ ID NO:25; or
서열번호 29에 제시된 HCDR1, 서열번호 30에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 30 and HCDR3 set forth in SEQ ID NO: 31
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편은 항체 중쇄 가변 영역을 포함하고, 여기서 상기 항체 중쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the anti-B7-H4 antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region wherein the antibody heavy chain variable region comprises
서열번호 43에 제시된 HCDR1, 서열번호 44에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 또는HCDR1 set forth in SEQ ID NO: 43, HCDR2 set forth in SEQ ID NO: 44 and HCDR3 set forth in SEQ ID NO: 25; or
서열번호 29에 제시된 HCDR1, 서열번호 45에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 45 and HCDR3 set forth in SEQ ID NO: 31
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab의 항체 중쇄 가변 영역은 하기 (1) 내지 (4)로 이루어진 군으로부터 선택된 어느 하나의 CDR을 포함한다:In one embodiment of the present invention, in the antibody-drug conjugate of Formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the antibody heavy chain variable region of Ab consists of the following (1) to (4) comprising any one CDR selected from the group:
(1) 서열번호 3에 제시된 HCDR1, 서열번호 4에 제시된 HCDR2 및 서열번호 5에 제시된 HCDR3;(1) HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 and HCDR3 shown in SEQ ID NO: 5;
(2) 서열번호 9에 제시된 HCDR1, 서열번호 10에 제시된 HCDR2 및 서열번호 11에 제시된 HCDR3;(2) HCDR1 shown in SEQ ID NO: 9, HCDR2 shown in SEQ ID NO: 10 and HCDR3 shown in SEQ ID NO: 11;
(3) 서열번호 23에 제시된 HCDR1, 서열번호 24에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 및(3) HCDR1 set forth in SEQ ID NO:23, HCDR2 set forth in SEQ ID NO:24 and HCDR3 set forth in SEQ ID NO:25; and
(4) 서열번호 29에 제시된 HCDR1, 서열번호 30에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3.(4) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 30 and HCDR3 set forth in SEQ ID NO: 31.
상기 Ab의 항체 중쇄 가변 영역은 또한 하기 (5) 내지 (6)으로 이루어진 군으로부터 선택된 CDR을 포함할 수 있다:The antibody heavy chain variable region of said Ab may also comprise a CDR selected from the group consisting of (5) to (6):
(5) 서열번호 43에 제시된 HCDR1, 서열번호 44에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 및(5) HCDR1 set forth in SEQ ID NO:43, HCDR2 set forth in SEQ ID NO:44 and HCDR3 set forth in SEQ ID NO:25; and
(6) 서열번호 29에 제시된 HCDR1, 서열번호 45에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3.(6) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 45 and HCDR3 set forth in SEQ ID NO: 31.
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편은 항체 경쇄 가변 영역을 포함하고, 여기서 상기 항체 경쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the anti-B7-H4 antibody or antigen-binding fragment thereof comprises an antibody light chain variable region wherein the antibody light chain variable region comprises
각각 서열번호 6, 서열번호 7 및 서열번호 8에 제시된 LCDR1, LCDR2 및 LCDR3; 또는LCDR1, LCDR2 and LCDR3 set forth in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, respectively; or
각각 서열번호 12, 서열번호 13 및 서열번호 14에 제시된 LCDR1, LCDR2 및 LCDR3LCDR1, LCDR2 and LCDR3 set forth in SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, respectively
을 포함한다.includes
본 발명의 일부 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편은 항체 경쇄 가변 영역을 포함하고, 여기서 상기 항체 경쇄 가변 영역은In some embodiments of the present invention, in the antibody-drug conjugate of Formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the anti-B7-H4 antibody or antigen-binding fragment thereof comprises an antibody light chain variable region wherein said antibody light chain variable region comprises
각각 서열번호 26, 서열번호 27 및 서열번호 28에 제시된 LCDR1, LCDR2 및 LCDR3; 또는LCDR1, LCDR2 and LCDR3 set forth in SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, respectively; or
각각 서열번호 32, 서열번호 33 및 서열번호 34에 제시된 LCDR1, LCDR2 및 LCDR3LCDR1, LCDR2 and LCDR3 set forth in SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, respectively
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab의 항체 중쇄 가변 영역은 하기 (1) 내지 (4)로 이루어진 군으로부터 선택된 어느 하나의 CDR을 포함한다:In one embodiment of the present invention, in the antibody-drug conjugate of Formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the antibody heavy chain variable region of Ab consists of the following (1) to (4) comprising any one CDR selected from the group:
(1) 서열번호 6에 제시된 LCDR1, 서열번호 7에 제시된 LCDR2 및 서열번호 8에 제시된 LCDR3;(1) LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7 and LCDR3 shown in SEQ ID NO: 8;
(2) 서열번호 12에 제시된 LCDR1, 서열번호 13에 제시된 LCDR2 및 서열번호 14에 제시된 LCDR3;(2) LCDR1 set forth in SEQ ID NO: 12, LCDR2 set forth in SEQ ID NO: 13 and LCDR3 set forth in SEQ ID NO: 14;
(3) 서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3; 및(3) LCDR1 set forth in SEQ ID NO:26, LCDR2 set forth in SEQ ID NO:27 and LCDR3 set forth in SEQ ID NO:28; and
(4) 서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3.(4) LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34.
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편의 중쇄 및 경쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof, as described above, the heavy and light chains of the anti-B7-H4 antibody or antigen-binding fragment thereof are variable area is
(1) 각각 서열번호 3에 제시된 HCDR1, 서열번호 4에 제시된 HCDR2 및 서열번호 5에 제시된 HCDR3; 또는(1) HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 and HCDR3 shown in SEQ ID NO: 5, respectively; or
서열번호 6에 제시된 LCDR1, 서열번호 7에 제시된 LCDR2 및 서열번호 8에 제시된 LCDR3; 또는LCDR1 set forth in SEQ ID NO: 6, LCDR2 set forth in SEQ ID NO: 7 and LCDR3 set forth in SEQ ID NO: 8; or
(2) 각각 서열번호 9에 제시된 HCDR1, 서열번호 10에 제시된 HCDR2 및 서열번호 11에 제시된 HCDR3; 또는(2) HCDR1 shown in SEQ ID NO: 9, HCDR2 shown in SEQ ID NO: 10 and HCDR3 shown in SEQ ID NO: 11, respectively; or
서열번호 12에 제시된 LCDR1, 서열번호 13에 제시된 LCDR2 및 서열번호 14에 제시된 LCDR3LCDR1 shown in SEQ ID NO: 12, LCDR2 shown in SEQ ID NO: 13 and LCDR3 shown in SEQ ID NO: 14
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편의 중쇄 및 경쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof, as described above, the heavy and light chains of the anti-B7-H4 antibody or antigen-binding fragment thereof are variable area is
(3) 서열번호 23에 제시된 HCDR1, 서열번호 24에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 또는(3) HCDR1 set forth in SEQ ID NO:23, HCDR2 set forth in SEQ ID NO:24 and HCDR3 set forth in SEQ ID NO:25; or
서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3; 또는LCDR1 shown in SEQ ID NO:26, LCDR2 shown in SEQ ID NO:27 and LCDR3 shown in SEQ ID NO:28; or
(4) 서열번호 29에 제시된 HCDR1, 서열번호 30에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3; 또는(4) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 30 and HCDR3 set forth in SEQ ID NO: 31; or
서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체 또는 이의 항원-결합 단편의 중쇄 및 경쇄 가변 영역은In one embodiment of the present invention, in the antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof, as described above, the heavy and light chains of the anti-B7-H4 antibody or antigen-binding fragment thereof are variable area is
(5) 각각 서열번호 43에 제시된 HCDR1, 서열번호 44에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 또는(5) HCDR1 set forth in SEQ ID NO: 43, HCDR2 set forth in SEQ ID NO: 44 and HCDR3 set forth in SEQ ID NO: 25, respectively; or
서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3; 또는LCDR1 shown in SEQ ID NO:26, LCDR2 shown in SEQ ID NO:27 and LCDR3 shown in SEQ ID NO:28; or
(6) 각각 서열번호 29에 제시된 HCDR1, 서열번호 45에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3; 또는(6) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 45 and HCDR3 set forth in SEQ ID NO: 31, respectively; or
서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34
을 포함한다.includes
본 발명의 하나의 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab의 항체 중쇄 가변 영역 및 항체 경쇄 가변 영역은 하기 (1) 내지 (4)로 이루어진 군으로부터 선택된 어느 하나의 CDR을 포함한다:In one embodiment of the present invention, in the antibody-drug conjugate of Formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the antibody heavy chain variable region and the antibody light chain variable region of Ab are selected from the following (1) to (4) comprises any one CDR selected from the group consisting of:
(1) 서열번호 3에 제시된 HCDR1, 서열번호 4에 제시된 HCDR2 및 서열번호 5에 제시된 HCDR3; 및(1) HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 and HCDR3 shown in SEQ ID NO: 5; and
서열번호 6에 제시된 LCDR1, 서열번호 7에 제시된 LCDR2 및 서열번호 8에 제시된 LCDR3;LCDR1 set forth in SEQ ID NO: 6, LCDR2 set forth in SEQ ID NO: 7 and LCDR3 set forth in SEQ ID NO: 8;
(2) 서열번호 9에 제시된 HCDR1, 서열번호 10에 제시된 HCDR2 및 서열번호 11에 제시된 HCDR3; 및(2) HCDR1 shown in SEQ ID NO: 9, HCDR2 shown in SEQ ID NO: 10 and HCDR3 shown in SEQ ID NO: 11; and
서열번호 12에 제시된 LCDR1, 서열번호 13에 제시된 LCDR2 및 서열번호 14에 제시된 LCDR3;LCDR1 shown in SEQ ID NO: 12, LCDR2 shown in SEQ ID NO: 13 and LCDR3 shown in SEQ ID NO: 14;
(3) 서열번호 23에 제시된 HCDR1, 서열번호 24에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 및(3) HCDR1 set forth in SEQ ID NO:23, HCDR2 set forth in SEQ ID NO:24 and HCDR3 set forth in SEQ ID NO:25; and
서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3; 및LCDR1 shown in SEQ ID NO:26, LCDR2 shown in SEQ ID NO:27 and LCDR3 shown in SEQ ID NO:28; and
(4) 서열번호 29에 제시된 HCDR1, 서열번호 30에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3; 및(4) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 30 and HCDR3 set forth in SEQ ID NO: 31; and
서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3.LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34.
상기 Ab의 항체 중쇄 가변 영역 및 항체 경쇄 가변 영역은 또한 하기 (5) 또는 (6)으로 이루어진 군으로부터 선택된 CDR을 포함할 수 있다:The antibody heavy chain variable region and antibody light chain variable region of said Ab may also comprise a CDR selected from the group consisting of (5) or (6):
(5) 서열번호 43에 제시된 HCDR1, 서열번호 44에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 및(5) HCDR1 set forth in SEQ ID NO:43, HCDR2 set forth in SEQ ID NO:44 and HCDR3 set forth in SEQ ID NO:25; and
서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3;LCDR1 shown in SEQ ID NO:26, LCDR2 shown in SEQ ID NO:27 and LCDR3 shown in SEQ ID NO:28;
(6) 서열번호 29에 제시된 HCDR1, 서열번호 45에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3; 및(6) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 45 and HCDR3 set forth in SEQ ID NO: 31; and
서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3.LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 쥐 항체 또는 이의 단편, 키메라 항체 또는 이의 단편, 인간 항체 또는 이의 단편, 및 인간화된 항체 또는 이의 단편이다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is a murine antibody or fragment thereof, a chimeric antibody or fragment thereof, a human antibody or fragment thereof, and A humanized antibody or fragment thereof.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 경쇄 프레임워크 영역 및 중쇄 프레임워크 영역 서열을 추가로 포함하고, 이들은 각각 인간 생식세포계열 경쇄 및 중쇄 서열 또는 이의 돌연변이 서열로부터 유래되고;In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab further comprises a light chain framework region and a heavy chain framework region sequence, each of which is a human derived from germline light and heavy chain sequences or mutant sequences thereof;
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 중쇄 불변 영역을 추가로 포함하고, 상기 중쇄 불변 영역은 인간 IgG1 또는 이의 변이체, IgG2 또는 이의 변이체, IgG3 또는 이의 변이체, 또는 IgG4 또는 이의 변이체로부터 유래된 영역, 바람직하게는 인간 IgG1, IgG2 또는 IgG4로부터 유래된 영역, 보다 바람직하게는 아미노산 돌연변이 후에 증대된 ADCC 독성을 갖는 IgG1 중쇄 불변 영역, 가장 바람직하게는 서열번호 54에 제시된 중쇄 불변 영역을 포함하고;In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab further comprises a heavy chain constant region, wherein the heavy chain constant region is human IgG1 or a variant thereof. , IgG2 or variants thereof, IgG3 or variants thereof, or regions derived from IgG4 or variants thereof, preferably regions derived from human IgG1, IgG2 or IgG4, more preferably IgG1 heavy chain with enhanced ADCC toxicity after amino acid mutation a constant region, most preferably a heavy chain constant region set forth in SEQ ID NO:54;
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 인간 κ 쇄, λ 쇄 또는 이의 변이체로부터 유래된 경쇄 불변 영역, 바람직하게는 인간 κ 쇄로부터 유래된 상기 영역, 보다 바람직하게는 서열번호 55에 제시된 경쇄 불변 영역을 추가로 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is a light chain constant region derived from a human κ chain, a λ chain or a variant thereof, preferably It further comprises said region derived from a human κ chain, more preferably a light chain constant region set forth in SEQ ID NO:55.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 16 또는 서열번호 18을 갖는 경쇄 가변 영역을 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab comprises a light chain variable region having the following sequence: SEQ ID NO: 16 or SEQ ID NO: 18 .
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 16, 서열번호 18, 서열번호 36 또는 서열번호 38을 갖는 경쇄 가변 영역, 또는 서열번호 16, 서열번호 18, 서열번호 36 또는 서열번호 38과 적어도 70%, 75%, 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 경쇄 가변 영역을 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is of the following sequence: SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 36 or SEQ ID NO: 38 a light chain variable region having at least 70%, 75%, 80%, 85%, 90%, 95% or 99% homology to SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 36 or SEQ ID NO: 38 variable regions.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 15 또는 서열번호 17을 갖는 중쇄 가변 영역을 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab comprises a heavy chain variable region having the following sequence: SEQ ID NO: 15 or SEQ ID NO: 17 .
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 15, 서열번호 17, 서열번호 35 또는 서열번호 37을 갖는 중쇄 가변 영역, 또는 서열번호 15, 서열번호 17, 서열번호 35 또는 서열번호 37과 적어도 70%, 75%, 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 중쇄 가변 영역을 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is of the following sequence: SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 35 or SEQ ID NO: 37 a heavy chain variable region having at least 70%, 75%, 80%, 85%, 90%, 95% or 99% homology to SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 35 or SEQ ID NO: 37 variable regions.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab의 중쇄 가변 영역 및 경쇄 가변 영역은 하기로 이루어진 군으로부터 선택된 어느 하나이다:In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the heavy chain variable region and the light chain variable region of Ab are any one selected from the group consisting of:
(1) 서열번호 15에 제시된 중쇄 가변 영역 및 서열번호 16에 제시된 경쇄 가변 영역;(1) a heavy chain variable region set forth in SEQ ID NO: 15 and a light chain variable region set forth in SEQ ID NO: 16;
(2) 서열번호 17에 제시된 중쇄 가변 영역 및 서열번호 18에 제시된 경쇄 가변 영역.(2) a heavy chain variable region set forth in SEQ ID NO: 17 and a light chain variable region set forth in SEQ ID NO: 18.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab의 중쇄 가변 영역 및 경쇄 가변 영역은 하기로 이루어진 군으로부터 선택된 어느 하나이다:In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the heavy chain variable region and the light chain variable region of Ab are any one selected from the group consisting of:
(1) 서열번호 15에 제시된 중쇄 가변 영역 및 서열번호 16에 제시된 경쇄 가변 영역;(1) a heavy chain variable region set forth in SEQ ID NO: 15 and a light chain variable region set forth in SEQ ID NO: 16;
(2) 서열번호 17에 제시된 중쇄 가변 영역 및 서열번호 18에 제시된 경쇄 가변 영역;(2) a heavy chain variable region set forth in SEQ ID NO: 17 and a light chain variable region set forth in SEQ ID NO: 18;
(3) 서열번호 35에 제시된 중쇄 가변 영역 및 서열번호 36에 제시된 경쇄 가변 영역; 및(3) a heavy chain variable region set forth in SEQ ID NO: 35 and a light chain variable region set forth in SEQ ID NO: 36; and
(4) 서열번호 37에 제시된 중쇄 가변 영역 및 서열번호 38에 제시된 경쇄 가변 영역.(4) a heavy chain variable region set forth in SEQ ID NO: 37 and a light chain variable region set forth in SEQ ID NO: 38.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 20 또는 서열번호 22를 갖는 경쇄 가변 영역을 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab comprises a light chain variable region having the following sequence: SEQ ID NO: 20 or SEQ ID NO: 22 .
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 20, 서열번호 22, 서열번호 40 또는 서열번호 42를 갖는 경쇄 또는 서열번호 20, 또는 서열번호 22, 서열번호 40 또는 서열번호 42와 적어도 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 전장 경쇄를 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is of the following sequence: SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 40 or SEQ ID NO: 42 or a full-length light chain having at least 80%, 85%, 90%, 95% or 99% homology to SEQ ID NO: 20, or SEQ ID NO: 22, SEQ ID NO: 40 or SEQ ID NO: 42.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 19 또는 서열번호 21을 갖는 중쇄를 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab comprises a heavy chain having the following sequence: SEQ ID NO: 19 or SEQ ID NO: 21.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는 하기의 서열: 서열번호 19, 서열번호 21, 서열번호 39, 서열번호 41을 갖는 중쇄 또는 서열번호 19, 서열번호 21, 서열번호 39, 서열번호 41과 적어도 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 전장 중쇄를 포함한다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab comprises the following sequences: SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 39, SEQ ID NO: 41 or a full-length heavy chain having at least 80%, 85%, 90%, 95% or 99% homology to SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 39, SEQ ID NO: 41.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is
(1) 서열번호 20의 경쇄 및 서열번호 19의 중쇄; 또는(1) a light chain of SEQ ID NO: 20 and a heavy chain of SEQ ID NO: 19; or
(2) 서열번호 22의 경쇄 및 서열번호 21의 중쇄(2) the light chain of SEQ ID NO: 22 and the heavy chain of SEQ ID NO: 21
를 포함한다.includes
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, Ab는In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, Ab is
(1) 서열번호 20의 경쇄 및 서열번호 19의 중쇄; 또는(1) a light chain of SEQ ID NO: 20 and a heavy chain of SEQ ID NO: 19; or
(2) 서열번호 22의 경쇄 및 서열번호 21의 중쇄; 또는(2) a light chain of SEQ ID NO: 22 and a heavy chain of SEQ ID NO: 21; or
(3) 서열번호 40의 경쇄 및 서열번호 39의 중쇄; 또는(3) a light chain of SEQ ID NO: 40 and a heavy chain of SEQ ID NO: 39; or
(4) 서열번호 42의 경쇄 및 서열번호 41의 중쇄(4) the light chain of SEQ ID NO: 42 and the heavy chain of SEQ ID NO: 41
를 포함한다.includes
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 항-B7-H4 항체의 항원-결합 단편은 Fab, Fab', F(ab')2, 단쇄 항체(scFv), 이량체화된 V 영역(다이아바디(diabody)), 다이설파이드 결합 안정화된 V 영역(dsFv) 및 CDR을 포함하는 펩타이드의 항원-결합 단편으로 이루어진 군으로부터 선택된다.In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the antigen-binding fragment of the anti-B7-H4 antibody is Fab, Fab', F(ab' ) 2 , an antigen-binding fragment of a peptide comprising a single chain antibody (scFv), a dimerized V region (diabody), a disulfide bond stabilized V region (dsFv) and a CDR.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 세포독성 약물은 독소, 화학요법제, 항생제, 방사성동위원소 및 핵산분해 효소; 바람직하게는 세포 분열을 억제하는 튜불린 억제제 또는 DNA 국소이성화효소 억제제; 보다 바람직하게는 DM1, DM3, DM4, SN-38, MMAF 및 MMAE; 더욱 바람직하게는 튜불린 억제제 SN-38, MMAE 및 MMAF로 이루어진 군으로부터 선택된다. 여기서, MMAF 및 SN-38의 구조는 하기의 식들에 나타낸 바와 같다:In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the cytotoxic drug is a toxin, a chemotherapeutic agent, an antibiotic, a radioisotope and a nuclease; Preferably, a tubulin inhibitor or a DNA topoisomerase inhibitor that inhibits cell division; more preferably DM1, DM3, DM4, SN-38, MMAF and MMAE; more preferably selected from the group consisting of the tubulin inhibitors SN-38, MMAE and MMAF. Here, the structures of MMAF and SN-38 are as shown in the following equations:
. .
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 세포독성 약물은 캄토테신 유도체, 바람직하게는 엑사테칸(Exatecan)으로부터 선택된다:In a preferred embodiment, in the antibody-drug conjugate of formula A as described above, or a pharmaceutically acceptable salt or solvate thereof, the cytotoxic drug is selected from camptothecin derivatives, preferably Exatecan:
. .
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a preferred embodiment, the antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof as described above is a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof:
[화학식 I][Formula I]
상기 식에서,In the above formula,
L1 및 L2는 링커 단위이고;L 1 and L 2 are linker units;
y는 1 내지 8로부터 선택되는 수, 바람직하게는 2 내지 4로부터 선택되는 수이고;y is a number selected from 1 to 8, preferably a number selected from 2 to 4;
Ab는 상기에서 정의된 바와 같은 항-B7-H4 항체 또는 이의 항원-결합 단편이다.Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof as defined above.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 II의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a preferred embodiment, the antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate of formula (II), or a pharmaceutically acceptable salt or solvate thereof:
[화학식 II][Formula II]
상기 식에서,In the above formula,
L1 및 L2는 링커 단위이고;L 1 and L 2 are linker units;
y는 1 내지 8로부터 선택되는 수, 바람직하게는 2 내지 4로부터 선택되는 수이고;y is a number selected from 1 to 8, preferably a number selected from 2 to 4;
Ab는 상기에서 정의된 바와 같은 항-B7-H4 항체 또는 이의 항원-결합 단편이다.Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof as defined above.
바람직한 실시태양에서, 상술한 바와 같은 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 III의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a preferred embodiment, the antibody-drug conjugate of formula (A) or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate of formula (III), or a pharmaceutically acceptable salt or solvate thereof:
[화학식 III][Formula III]
상기 식에서,In the above formula,
L1 및 L2는 링커 단위이고;L 1 and L 2 are linker units;
y는 1 내지 10로부터 선택되는 수, 바람직하게는 2 내지 8로부터 선택되는 수, 보다 바람직하게는 4 내지 8로부터 선택되는 수이거나;y is a number selected from 1 to 10, preferably a number selected from 2 to 8, more preferably a number selected from 4 to 8;
y는 2 내지 10으로부터 선택되는 수, 더욱 바람직하게는 6 내지 10으로부터 선택되는 수, 보다 바람직하게는 7 내지 9의 수, 가장 바람직하게는 7, 8, 9의 정수이고;y is a number selected from 2 to 10, more preferably a number selected from 6 to 10, more preferably a number from 7 to 9, most preferably an integer from 7, 8, 9;
Ab는 상기에서 정의된 바와 같은 항-B7-H4 항체 또는 이의 항원-결합 단편이다.Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof as defined above.
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, L1은 하기 화학식 B에 나타낸 바와 같다:In a preferred embodiment, in the antibody-drug conjugate as described above, or a pharmaceutically acceptable salt or solvate thereof, L 1 is as shown in Formula B:
[화학식 B][Formula B]
상기 식에서,In the above formula,
M1은 -CR1R2-이고;M 1 is —CR 1 R 2 —;
R1 및 R2는 동일하거나 상이하고, 수소, 알킬, 할로겐, 하이드록실 및 아미노로 이루어진 군으로부터 독립적으로 선택되고;R 1 and R 2 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl and amino;
N은 0 내지 5의 정수, 바람직하게는 1, 2 또는 3이다.N is an integer from 0 to 5, preferably 1, 2 or 3.
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, L2는 하기 화학식 C에 나타낸 바와 같다:In a preferred embodiment, in the antibody-drug conjugate as described above or a pharmaceutically acceptable salt or solvate thereof, L 2 is as shown in Formula (C):
[화학식 C][Formula C]
상기 식에서,In the above formula,
M2는 -CR4R5-이고;M 2 is —CR 4 R 5 —;
R3은 수소 원자, 할로겐, 하이드록실, 아미노, 알킬, 알콕실 및 사이클로알킬로 이루어진 군으로부터 선택되고;R 3 is selected from the group consisting of a hydrogen atom, halogen, hydroxyl, amino, alkyl, alkoxyl and cycloalkyl;
R4 및 R5는 동일하거나 상이하고, 수소, 알킬, 할로겐, 하이드록실 및 아미노로 이루어진 군으로부터 독립적으로 선택되고;R 4 and R 5 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl and amino;
m은 0 내지 5의 정수, 바람직하게는 1, 2 또는 3이다.m is an integer from 0 to 5, preferably 1, 2 or 3.
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, L2는 하기 화학식 D에 나타낸 바와 같다:In a preferred embodiment, in the antibody-drug conjugate as described above, or a pharmaceutically acceptable salt or solvate thereof, L 2 is as shown in Formula D:
[화학식 D][Formula D]
-K1-K2-K3-K4--K 1 -K 2 -K 3 -K 4 -
상기 식에서,In the above formula,
K1은 이고, s는 2 내지 8의 정수, 더욱 바람직하게는 4 내지 8의 정수, 보다 바람직하게는 4 내지 6의 정수이고;K 1 is , s is an integer from 2 to 8, more preferably an integer from 4 to 8, more preferably an integer from 4 to 6;
K2는 -NR1(CH2CH2O)pCH2CH2C(O)-, -NR1(CH2CH2O)pCH2C(O)-, -S(CH2)pC(O)- 또는 단일 결합이고, p는 1 내지 20, 바람직하게는 1 내지 6의 정수이고;K 2 is -NR 1 (CH 2 CH 2 O) p CH 2 CH 2 C(O)-, -NR 1 (CH 2 CH 2 O) p CH 2 C(O)-, -S(CH 2 ) p C(O)- or a single bond, p is an integer from 1 to 20, preferably from 1 to 6;
R1은 수소, 중수소, 하이드록실, 아미노, 알킬, 할로겐, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 선택되고;R 1 is selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, alkyl, halogen, haloalkyl, deuterated alkyl and hydroxyalkyl;
K3은 테트라펩타이드 잔기이고, 바람직하게는 상기 테트라펩타이드 잔기는 페닐알라닌, 글리신, 발린, 리신, 시트룰린, 세린, 글루타메이트 및 아스파테이트 중 2개 이상으로 이루어진 군으로부터 선택된 아미노산에 의해 형성된 펩타이드 잔기; 보다 바람직하게 테트라펩타이드 잔기 GGFG이고;K 3 is a tetrapeptide residue, preferably the tetrapeptide residue is a peptide residue formed by an amino acid selected from the group consisting of at least two of phenylalanine, glycine, valine, lysine, citrulline, serine, glutamate and aspartate; more preferably the tetrapeptide residue GGFG;
K4는 -NR2(CR3R4)t-이고, R2, R3 및 R4는 각각 독립적으로 수소, 중수소, 하이드록실, 아미노, 알킬, 할로겐, 할로알킬, 중수소화된 알킬 및 하이드록시알킬이고; t는 1 또는 2이고, K 4 is —NR 2 (CR 3 R 4 )t—, and R 2 , R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, amino, alkyl, halogen, haloalkyl, deuterated alkyl and hydride. hydroxyalkyl; t is 1 or 2,
바람직하게는 L2에 관하여,preferably with respect to L 2 ,
K1은 이고, s는 5이고;K 1 is and s is 5;
K2는 결합이고;K 2 is a bond;
K3은 테트라펩타이드 잔기 GGFG이고;K 3 is the tetrapeptide residue GGFG;
K4는 -NR2(CR3R4)t-이고, R2, R3 및 R4는 각각 독립적으로 수소, 중수소, 하이드록실, 아미노, C1-6 알킬, 할로겐, C1-6 할로알킬, C1-6 중수소화된 알킬 및 C1-6 하이드록시알킬이고, t는 1 또는 2이다.K 4 is —NR 2 (CR 3 R 4 )t-, and R 2 , R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, amino, C 1-6 alkyl, halogen, C 1-6 halo alkyl, C 1-6 deuterated alkyl and C 1-6 hydroxyalkyl, and t is 1 or 2.
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, 링커 단위 -L2-의 K1 말단은 Ab에 연결되고, K4 말단은 L1에 연결된다.In a preferred embodiment, in the antibody-drug conjugate as described above or a pharmaceutically acceptable salt or solvate thereof, the K 1 terminus of the linker unit -L 2 - is linked to Ab, and the K 4 terminus is linked to L 1 . do.
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, L1은 -O-(CRaRb)m-CR5R6-C(O)-, -O-CR5R6-(CRaRb)m-, -O-CR5R6-, -NH-(CRaRb)m-CR5R6-C(O)- 또는 -S-(CRaRb)m-CR5R6-C(O)-이고;In a preferred embodiment, in the antibody-drug conjugate as described above, or a pharmaceutically acceptable salt or solvate thereof, L 1 is -O-(CR a R b ) m -CR 5 R 6 -C(O)- , -O-CR 5 R 6 -(CR a R b ) m -, -O-CR 5 R 6 -, -NH-(CR a R b ) m -CR 5 R 6 -C(O)- or - S-(CR a R b ) m -CR 5 R 6 -C(O)-;
Ra 및 Rb는 각각 독립적으로 수소, 중수소, 할로겐 및 알킬로 이루어진 군으로부터 선택되고;R a and R b are each independently selected from the group consisting of hydrogen, deuterium, halogen and alkyl;
R5는 할로알킬 또는 사이클로알킬이고,R 5 is haloalkyl or cycloalkyl,
R6은 수소, 할로알킬 및 사이클로알킬로 이루어진 군으로부터 선택되거나,R 6 is selected from the group consisting of hydrogen, haloalkyl and cycloalkyl,
R5 및 R6 및 이들이 연결된 탄소 원자는 사이클로알킬을 형성하고;R 5 and R 6 and the carbon atom to which they are connected form a cycloalkyl;
m은 0, 1, 2, 3 또는 4이다.m is 0, 1, 2, 3 or 4.
바람직하게는, L1의 O 말단은 링커 단위 L2에 연결된다.Preferably, the O terminus of L 1 is connected to the linker unit L 2 .
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, L1은 하기 화학식 E에 나타낸 바와 같다:In a preferred embodiment, in the antibody-drug conjugate as described above, or a pharmaceutically acceptable salt or solvate thereof, L 1 is as shown in Formula E:
[화학식 E][Formula E]
상기 식에서,In the above formula,
R5는 할로알킬 또는 사이클로알킬이고,R 5 is haloalkyl or cycloalkyl,
R6은 수소, 할로알킬 및 사이클로알킬로 이루어진 군으로부터 선택되거나,R 6 is selected from the group consisting of hydrogen, haloalkyl and cycloalkyl,
R5 및 R6 및 이들이 연결된 탄소 원자는 사이클로알킬을 형성하고;R 5 and R 6 and the carbon atom to which they are connected form a cycloalkyl;
바람직하게는preferably
R5는 C1-6 할로알킬 및 C3-6 사이클로알킬로 이루어진 군으로부터 선택되고,R 5 is selected from the group consisting of C 1-6 haloalkyl and C 3-6 cycloalkyl,
R6은 수소, C1-6 할로알킬 및 사이클로알킬로 이루어진 군으로부터 선택되거나,R 6 is selected from the group consisting of hydrogen, C 1-6 haloalkyl and cycloalkyl,
R5 및 R6 및 이들이 연결된 탄소 원자는 C3-6 사이클로알킬을 형성하고;R 5 and R 6 and the carbon atom to which they are connected form a C 3-6 cycloalkyl;
m은 0 내지 4의 정수이고;m is an integer from 0 to 4;
보다 바람직하게는, 화학식 E는 하기의 치환기로 이루어진 군으로부터 선택된다:More preferably, formula E is selected from the group consisting of the following substituents:
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물에서, -L2-L1-은 하기의 구조이다:In a more preferred embodiment, in the antibody-drug conjugate as described above, or a pharmaceutically acceptable salt or solvate thereof, -L 2 -L 1 - is of the structure:
상기 식에서,In the above formula,
K2는 결합이고;K 2 is a bond;
K3은 테트라펩타이드 잔기 GGFG이고;K 3 is the tetrapeptide residue GGFG;
R5는 할로알킬 또는 C3-6 사이클로알킬이고,R 5 is haloalkyl or C 3-6 cycloalkyl,
R6은 수소, 할로알킬 및 C3-6 사이클로알킬로 이루어진 군으로부터 선택되거나,R 6 is selected from the group consisting of hydrogen, haloalkyl and C 3-6 cycloalkyl,
R5 및 R6 및 이들이 연결된 탄소 원자는 C3-6 사이클로알킬을 형성하고;R 5 and R 6 and the carbon atom to which they are connected form a C 3-6 cycloalkyl;
R2, R3 및 R4는 각각 독립적으로 수소 또는 알킬이고;R 2 , R 3 and R 4 are each independently hydrogen or alkyl;
s는 2 내지 8의 정수이고; 바람직하게는, s는 4, 5 또는 6이고;s is an integer from 2 to 8; Preferably, s is 4, 5 or 6;
m은 0 내지 4의 정수이고;m is an integer from 0 to 4;
바람직하게는, 상기 -L2-L1-은 하기의 구조로 이루어진 군으로부터 선택된다:Preferably, said -L 2 -L 1 - is selected from the group consisting of:
바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 IV에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a preferred embodiment, the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as shown in Formula IV:
[화학식 IV][Formula IV]
상기 식에서,In the above formula,
W는 C1-8 알킬, C1-8 알킬-사이클로알킬 또는 1 내지 8개의 원자의 선형 헤테로알킬로 이루어진 군으로부터 선택되고, 상기 헤테로알킬은 N, O 또는 S로 이루어진 군으로부터 선택된 1 내지 3개의 헤테로원자를 포함하고, 여기서 상기 C1-8 알킬, 사이클로알킬 또는 선형 헤테로알킬은 각각 독립적으로 할로겐, 하이드록실, 시아노, 아미노, 알킬, 클로로알킬, 중수소화된 알킬, 알콕실 및 사이클로알킬로 이루어진 군으로부터 선택된 하나 이상의 치환기로 임의로 추가로 치환되고;W is selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl-cycloalkyl or linear heteroalkyl of 1 to 8 atoms, wherein said heteroalkyl is 1 to 3 selected from the group consisting of N, O or S heteroatoms, wherein each of said C 1-8 alkyl, cycloalkyl or linear heteroalkyl is independently halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxyl and cycloalkyl optionally further substituted with one or more substituents selected from the group consisting of;
K2는 -NR1(CH2CH2O)p1CH2CH2C(O)-, -NR1(CH2CH2O)p1CH2C(O)-, -S(CH2)p1C(O)- 및 결합으로 이루어진 군으로부터 선택되고, R1은 수소 원자, 알킬, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 선택되고, p1은 1 내지 20의 정수이고;K 2 is -NR 1 (CH 2 CH 2 O) p1 CH 2 CH 2 C(O)-, -NR 1 (CH 2 CH 2 O) p1 CH 2 C(O)-, -S(CH 2 ) p1 C(O)— and a bond, R 1 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl, p 1 is an integer from 1 to 20;
K3은 2 내지 7개의 아미노산으로 이루어진 펩타이드 잔기이고, 상기 아미노산은 치환되거나 비치환될 수 있다. 치환되는 경우, 상기 치환기는 임의의 이용가능한 부착점에서 치환될 수 있고, 상기 치환기는 할로겐, 하이드록실, 시아노, 아미노, 알킬, 클로로알킬, 중수소화된 알킬, 알콕실 및 사이클로알킬로 이루어진 군으로부터 독립적으로 선택된 하나 이상이고;K 3 is a peptide residue consisting of 2 to 7 amino acids, which may be substituted or unsubstituted. When substituted, said substituent may be substituted at any available point of attachment, said substituent being from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxyl and cycloalkyl. at least one independently selected from;
R2는 수소 원자, 알킬, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 독립적으로 선택되고;R 2 is independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl;
R3 및 R4는 각각 독립적으로 수소 원자, 할로겐, 알킬, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 선택되고;R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl;
R5는 할로겐, 할로알킬, 중수소화된 알킬, 사이클로알킬, 헤테로사이클릴, 아릴 및 헤테로아릴로 이루어진 군으로부터 선택되고,R 5 is selected from the group consisting of halogen, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R6은 수소 원자, 할로겐, 할로알킬, 중수소화된 알킬, 사이클로알킬, 헤테로사이클릴, 아릴 및 헤테로아릴로 이루어진 군으로부터 선택되거나,R 6 is selected from the group consisting of a hydrogen atom, halogen, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5 및 R6 및 이들이 연결된 탄소 원자는 사이클로알킬 또는 헤테로사이클릴을 형성하고;R 5 and R 6 and the carbon atom to which they are connected form a cycloalkyl or heterocyclyl;
m은 0 내지 4의 정수이고;m is an integer from 0 to 4;
y는 1 내지 10이고 y는 소수 또는 정수이고, 바람직하게는 y는 2 내지 10의 수이고, 보다 바람직하게는 y는 4 내지 10의 수, 더욱 바람직하게는 6 내지 9의 수, 가장 바람직하게는 7, 8 또는 9의 정수이고;y is 1 to 10 and y is a prime number or integer, preferably y is a number from 2 to 10, more preferably y is a number from 4 to 10, more preferably a number from 6 to 9, most preferably is an integer of 7, 8 or 9;
Ab는 항-B7-H4 항체 또는 이의 항원-결합 단편이다.Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof.
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 I-A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a more preferred embodiment, the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate of Formula I-A, or a pharmaceutically acceptable salt or solvate thereof:
[화학식 I-A][Formula I-A]
상기 식에서,In the above formula,
y는 1 내지 10이고, y는 소수 또는 정수이다.y is 1 to 10, and y is a decimal or integer.
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 I-B의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a more preferred embodiment, the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate of formula I-B, or a pharmaceutically acceptable salt or solvate thereof:
[화학식 I-B][Formula I-B]
상기 식에서,In the above formula,
y는 1 내지 10이고, y는 소수 또는 정수이다.y is 1 to 10, and y is a decimal or integer.
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 II-A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a more preferred embodiment, the antibody-drug conjugate as described above or a pharmaceutically acceptable salt or solvate thereof is an antibody-drug conjugate of Formula II-A, or a pharmaceutically acceptable salt or solvate thereof:
[화학식 II-A][Formula II-A]
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 II-B의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a more preferred embodiment, the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate of Formula II-B, or a pharmaceutically acceptable salt or solvate thereof:
[화학식 II-B][Formula II-B]
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기 화학식 IV-A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물이다:In a more preferred embodiment, the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as described above is an antibody-drug conjugate of Formula IV-A, or a pharmaceutically acceptable salt or solvate thereof:
[화학식 IV-A][Formula IV-A]
상기 식에서,In the above formula,
s는 2 내지 8의 정수이고, R2 내지 R6, m 및 y는 상기 화학식 IV에 정의된 바와 같고;s is an integer from 2 to 8, R 2 to R 6 , m and y are as defined in Formula IV above;
바람직하게는, s는 4, 5 또는 6의 정수이고, y는 4 내지 10의 수, 바람직하게는 6 내지 9의 수, 및 보다 바람직하게는 7 또는 8이다.Preferably, s is an integer of 4, 5 or 6, y is a number from 4 to 10, preferably a number from 6 to 9, and more preferably 7 or 8.
보다 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기의 화합물들로 이루어진 군으로부터 선택된다:In a more preferred embodiment, the antibody-drug conjugate as described above or a pharmaceutically acceptable salt or solvate thereof is selected from the group consisting of:
가장 바람직한 실시태양에서, 상술한 바와 같은 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물은 하기의 화합물들로 이루어진 군으로부터 선택된다:In a most preferred embodiment, the antibody-drug conjugate as described above or a pharmaceutically acceptable salt or solvate thereof is selected from the group consisting of:
상기 식에서,In the above formula,
y는 1 내지 10으로부터 선택되는 수, 바람직하게는 2 내지 10으로부터 선택되는 수, 추가로 6 내지 10으로부터 선택되는 수, 보다 바람직하게는 7 내지 9의 수, 가장 바람직하게는 7, 8, 9의 정수이거나; y는 2 내지 10으로부터 선택되는 수, 바람직하게는 4 내지 8의 수, 보다 바람직하게는 6 내지 8의 수, 더욱 바람직하게는 7 내지 8의 수, 가장 바람직하게는 8이다.y is a number selected from 1 to 10, preferably a number selected from 2 to 10, further a number selected from 6 to 10, more preferably a number from 7 to 9, most preferably 7, 8, 9 is an integer of; y is a number selected from 2 to 10, preferably a number from 4 to 8, more preferably a number from 6 to 8, even more preferably a number from 7 to 8, most preferably 8.
바람직한 실시태양에서, 본 발명은 하기의 단계들을 포함하는, 화학식 IV에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물의 제조 방법에 관한 것으로서, Ab가 환원될 때, 화학식 F에 제시된 화합물과 커플링 반응을 수행하여 화학식 IV에 제시된 화합물을 제조한다:In a preferred embodiment, the present invention relates to a method for preparing an antibody-drug conjugate represented by formula (IV), or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: The compound shown in Formula IV is prepared by performing a coupling reaction with the compound shown:
상기 식에서,In the above formula,
Ab는 항-B7-H4 항체 또는 이의 항원-결합 단편이고;Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof;
W, K2, K3, R2 내지 R6, m 및 y는 화학식 IV에 정의된 바와 같다.W, K 2 , K 3 , R 2 to R 6 , m and y are as defined in formula IV.
바람직한 실시태양에서, 화학식 F에 제시된 화합물이 하기 화학식 F-1에 제시된 화합물 또는 이의 호변이성질체, 메소머, 라세메이트, 거울상이성질체, 부분입체이성질체 또는 이들의 혼합 형태, 또는 이들의 약학적으로 허용가능한 염이다:In a preferred embodiment, the compound represented by formula F is the compound represented by formula F-1 It is salt:
[화학식 F-1][Formula F-1]
상기 식에서,In the above formula,
K2, K3, R2 내지 R6, s 및 m은 상기 -L2-L1-에 정의된 바와 같다.K 2 , K 3 , R 2 to R 6 , s and m are as defined in -L 2 -L 1 - above.
바람직한 실시태양에서, 화학식 F 또는 화학식 F-1에 제시된 화합물은 하기로 이루어진 군으로부터 선택된다:In a preferred embodiment, the compound represented by Formula F or Formula F-1 is selected from the group consisting of:
. .
바람직한 실시태양에서, 본 발명은 본 발명 중 어느 하나에 따른 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물, 및 하나 이상의 약학적으로 허용가능한 부형제, 희석제 또는 담체를 포함하는 약학 조성물에 관한 것이다.In a preferred embodiment, the present invention provides a pharmaceutical composition comprising an antibody-drug conjugate according to any one of the present invention or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers. it's about
바람직한 실시태양에서, 본 발명은 인간 B7-H4와 관련된 질병의 치료를 위한 약제, 바람직하게는 높은 B7-H4 발현을 갖는 암의 치료를 위한 약제의 제조에서 화학식 A의 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물, 또는 이의 약학 조성물의 용도에 관한 것이다.In a preferred embodiment, the present invention relates to an antibody-drug conjugate of formula (A) or a pharmaceutical thereof in the manufacture of a medicament for the treatment of a disease associated with human B7-H4, preferably a medicament for the treatment of a cancer having high B7-H4 expression. to the use of a chemically acceptable salt or solvate, or a pharmaceutical composition thereof.
보다 바람직한 실시태양에서, 상기 암은 인간 뇌의 성상모세포종, 인간 인두암, 부신 종양, AIDS-관련 암, 폐포 연부 육종, 성상세포종, 방광암, 골암, 뇌 및 척수암, 전이성 뇌종양, 유방암, 경동맥체종양, 자궁경부암, 연골육종, 척색종, 신장의 발색세포암종(chromophore cell carcinoma), 투명세포암종, 결장암, 결장직장암, 결합조직 증식성 소원형세포종양, 뇌실막종, 유잉육종, 골외점액 연골육종, 골성 불완전 섬유원증, 골의 섬유성 이형성증, 담낭 또는 담관암종, 위암, 임신성 융모성 질환, 생식 세포 종양, 두경부암, 간세포 암종, 섬 세포 종양, 카포시 육종, 신장암, 백혈병, 지방육종/악성 지방종 종양, 간암, 림프종, 폐암, 수모세포종, 흑색종, 수막종, 다발성 내분비종양, 다발성 골수종, 골수이형성 증후군, 신경모세포종, 신경내분비종양, 난소암, 췌장암, 갑상선 유두암, 부갑상선 선종, 소아암, 말초신경초종, 갈색세포종(pheocytoma), 뇌하수체종양, 전립선암, 후포도막흑색종, 신장전이암, 횡문근종양, 횡문근육종, 육종, 피부암, 연조직 육종, 편평 세포 암종, 활액 육종, 고환암, 흉선암, 갑상선 전이암 및 자궁암으로 이루어진 군으로부터 선택된다.In a more preferred embodiment, the cancer is astroblastoma of the human brain, human pharyngeal cancer, adrenal tumor, AIDS-related cancer, alveolar soft sarcoma, astrocytoma, bladder cancer, bone cancer, brain and spinal cord cancer, metastatic brain tumor, breast cancer, carotid body Tumor, cervical cancer, chondrosarcoma, chordoma, chromophore cell carcinoma of the kidney, clear cell carcinoma, colon cancer, colorectal cancer, connective tissue proliferative small cell tumor, ependymoma, Ewing's sarcoma, extraosseous mucinous chondrosarcoma , osseous incomplete fibrosis, fibrous dysplasia of bone, gallbladder or cholangiocarcinoma, gastric cancer, gestational villous disease, germ cell tumor, head and neck cancer, hepatocellular carcinoma, islet cell tumor, Kaposi's sarcoma, renal cancer, leukemia, liposarcoma/malignancy Lipoma tumor, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine tumor, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumor, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid adenoma, childhood cancer, peripheral schwannoma , pheocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, renal metastasis, rhabdomyosarcoma, rhabdomyosarcoma, sarcoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, synovial sarcoma, testicular cancer, thymus cancer, thyroid metastasis and uterine cancer.
도 1: 항체-약물 접합체의 생체내 효능: hu2G6-MC-MMAF 및 hu2F7-MC-MMAF는 1.5 ㎎/㎏ 및 3 ㎎/㎏의 용량에서 MX-1 이종이식편 종양에 대해 억제 및 사멸 효과를 나타내었다.
도 2: 각각 2 및 4의 약물 부하를 갖는 hu2F7-MC-MMAF의 HPLC 스펙트럼.
도 3: 각각 2 및 4의 약물 부하를 갖는 hu2F7-MC-MMAF의 생체내 항-종양 효능.
도 4: 각각 2 및 4의 약물 부하를 갖는 hu2F7-MC-MMAF의 생체내 항-종양 효능. 도면은 21일째에 각 군의 마우스의 종양을 도시한다.Figure 1: In vivo efficacy of antibody-drug conjugates: hu2G6-MC-MMAF and hu2F7-MC-MMAF showed inhibitory and killing effects on MX-1 xenograft tumors at doses of 1.5 mg/kg and 3 mg/kg it was
Figure 2: HPLC spectra of hu2F7-MC-MMAF with drug loadings of 2 and 4, respectively.
Figure 3: In vivo anti-tumor efficacy of hu2F7-MC-MMAF with drug loadings of 2 and 4, respectively.
Figure 4: In vivo anti-tumor efficacy of hu2F7-MC-MMAF with drug loadings of 2 and 4, respectively. The figure depicts the tumors of mice in each group at
1. 용어1. Terminology
본 발명을 보다 쉽게 이해하기 위해서, 몇몇 기술 과학 용어들을 하기에 구체적으로 정의한다. 본 문서에서 달리 명확하게 정의되지 않는 한, 본원에 사용된 모든 다른 기술 과학 용어들은 본 발명이 속하는 분야의 통상적인 숙련가에 의해 통상적으로 이해되는 의미를 갖는다.In order to better understand the present invention, some technical and scientific terms are specifically defined below. Unless explicitly defined otherwise in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs.
본 발명에서 사용되는 아미노산의 3-문자 코드 및 1-문자 코드는 문헌[J. Biol. Chem, 243, p3558 (1968)]에 기재된 바와 같다.The three-letter codes and one-letter codes of amino acids used in the present invention are described in J. Biol. Chem, 243, p3558 (1968)].
본 발명에 기재된 "항체"란 용어는 쇄간 다이설파이드 결합에 의해 연결된 2개의 동일한 중쇄 및 2개의 동일한 경쇄로 이루어진 테트라펩타이드 쇄 구조인 면역글로불린을 지칭한다. 상기 면역글로불린 중쇄 불변 영역에서 아미노산의 조성 및 순서는 상이하고, 따라서 이들의 항원성도 또한 상이하다. 이에 따라, 면역글로불린을 5개의 유형(또한 면역글로불린의 아이소타입으로서 공지됨), 즉 IgM, IgD, IgG, IgA 및 IgE로 분류할 수 있고, 이들의 상응하는 중쇄는 각각 μ 쇄, δ 쇄, γ 쇄, α 쇄 및 ε 쇄이다. 동일한 유형의 Ig를 힌지 영역의 아미노산 조성의 차이 및 중쇄 다이설파이드 결합의 수 및 위치에 따라 상이한 하위부류로 분류할 수 있다. 예를 들어, IgG를 IgG1, IgG2, IgG3 및 IgG4로 분류할 수 있다. 경쇄는 불변 영역의 차이에 따라 κ 쇄 또는 λ 쇄로 분류된다. Ig의 각각의 5개 유형은 κ 쇄 또는 λ 쇄를 가질 수 있다.As used herein, the term "antibody" refers to an immunoglobulin, a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by an interchain disulfide bond. The composition and order of amino acids in the immunoglobulin heavy chain constant region are different, and therefore their antigenicity is also different. Accordingly, immunoglobulins can be classified into five types (also known as isotypes of immunoglobulins): IgM, IgD, IgG, IgA and IgE, whose corresponding heavy chains are each μ chain, δ chain, γ chain, α chain and ε chain. Igs of the same type can be classified into different subclasses according to differences in the amino acid composition of the hinge region and the number and position of heavy chain disulfide bonds. For example, IgG can be classified as IgG1, IgG2, IgG3 and IgG4. Light chains are classified into κ chains or λ chains according to differences in constant regions. Each of the five types of Ig can have either a κ chain or a λ chain.
본 발명에서, 본 발명의 항체 경쇄 가변 영역은 경쇄 불변 영역을 추가로 포함할 수 있고, 상기 영역은 인간 또는 쥐 κ, λ 쇄 또는 이들의 변이체를 포함한다.In the present invention, the antibody light chain variable region of the present invention may further comprise a light chain constant region, wherein the region comprises a human or murine κ, λ chain or a variant thereof.
본 발명에서, 본 발명의 항체 중쇄 가변 영역은 중쇄 불변 영역을 추가로 포함할 수 있고, 상기 영역은 인간 또는 쥐 IgG1, 2, 3, 4 또는 이들의 변이체를 포함한다.In the present invention, the antibody heavy chain variable region of the present invention may further comprise a heavy chain constant region, wherein the region comprises human or murine IgG1, 2, 3, 4 or variants thereof.
항체 중쇄 및 경쇄의 N-말단 부근의 약 110개 아미노산의 서열은 대단히 다양하고 가변 영역(V 영역)이고; C-말단 부근의 나머지 아미노산 서열은 비교적 안정하고 불변 영역(C 영역)이다. 상기 가변 영역은 3개의 고가변 영역(HVR) 및 비교적 보존된 서열을 갖는 4개의 프레임워크 영역(FR)을 포함한다. 상기 3개의 고가변 영역은 항체의 특이성을 결정하고, 또한 상보성 결정 영역(CDR)으로서 공지되어 있다. 각각의 경쇄 가변 영역(VL) 및 중쇄 가변 영역(VH)은 3개의 CDR 영역 및 4개의 FR 영역으로 이루어지고, 아미노 말단에서부터 카복실 말단으로 FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4의 순서로 배열된다. 상기 경쇄의 3개의 CDR 영역은 LCDR1, LCDR2 및 LCDR3을 지칭하고; 상기 중쇄의 3개의 CDR 영역은 HCDR1, HCDR2 및 HCDR3을 지칭한다. 본 발명의 항체 또는 항원-결합 단편의 VL 영역 및 VH 영역의 CDR 아미노산 잔기의 수 및 위치는 공지된 카밧(Kabat) 또는 코티아(Chothia) 넘버링 기준 및 카밧 또는 AbM 정의 기준(http://bioinf.org.uk/abs/)을 준수한다.The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains is highly variable and is a variable region (V region); The remaining amino acid sequence near the C-terminus is relatively stable and is a constant region (C region). The variable region comprises three hypervariable regions (HVRs) and four framework regions (FRs) with relatively conserved sequences. These three hypervariable regions determine the specificity of an antibody and are also known as complementarity determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDR regions and four FR regions, in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from amino terminus to carboxyl terminus. are arranged as the three CDR regions of the light chain refer to LCDR1, LCDR2 and LCDR3; The three CDR regions of the heavy chain refer to HCDR1, HCDR2 and HCDR3. The number and position of CDR amino acid residues in the VL region and VH region of the antibody or antigen-binding fragment of the present invention is determined by the known Kabat or Chothia numbering standards and Kabat or AbM definition standards (http://bioinf). .org.uk/abs/).
"항원 제시 세포" 또는 "APC"란 용어는 표면상의 MHC와 복합체를 형성하는 외부 항원을 제공하는 세포이다. T 세포는 상기와 같은 복합체를 인식하는 T 세포 수용체(TCR)를 이용한다. APC의 예로는 비제한적으로 수지상세포(DC), 말초 혈액 단핵세포(PBMC), 단핵세포, B 림프모세포 및 단핵세포-유래된 수지상세포(DC)가 있다. "항원 제시"란 용어는 APC가 항원을 포획하고 상기 항원을 T 세포에 의해, 예를 들어 MHC-I/MHC-II 접합체의 성분으로서 인식될 수 있게 하는 과정을 지칭한다.The term "antigen presenting cell" or "APC" is a cell presenting a foreign antigen that forms a complex with MHC on its surface. T cells use the T cell receptor (TCR) to recognize such complexes. Examples of APCs include, but are not limited to, dendritic cells (DC), peripheral blood mononuclear cells (PBMC), mononuclear cells, B lymphoblasts, and monocyte-derived dendritic cells (DC). The term "antigen presentation" refers to the process by which APCs capture an antigen and make it available for recognition by T cells, for example as a component of an MHC-I/MHC-II conjugate.
"B7-H4"란 용어는 4개의 Ig-유사 세포외 도메인을 갖는 I형 막관통 단백질인 인간 B7 단백질 패밀리(또한 CD276으로서 공지됨)의 구성원을 지칭한다. B7-H4는 항원-제시 세포 또는 암세포의 표면상에서 발현되는 면역 관문 단백질 중 하나이고, T 세포의 기능적 활성화에 억제 효과가 있다. "B7-H4"란 용어는 세포에 의해 자연적으로 발현되는 B7-H4의 임의의 변이체 또는 동형을 포함한다. 본 발명의 항체는 비-인간 종으로부터 유래된 B7-H4와 교차-반응할 수 있다. 또 다른 선택권으로서, 항체는 또한 인간 B7-H4에 특이적일 수 있고 다른 종과 교차-반응성을 나타내지 않을 수도 있다. B7-H4 또는 이의 임의의 변이체 또는 동형을, 이를 자연적으로 발현하는 세포 또는 조직으로부터 단리하거나, 당해 분야에 통상적으로 사용되는 기법 및 본원에 기재된 기법을 사용하는 재조합 기법에 의해 생성시킬 수 있다. 바람직하게는, 상기 항-B7-H4 항체는 통상적인 글리코실화 패턴을 갖는 인간 B7-H4를 표적화한다.The term “B7-H4” refers to a member of the human B7 protein family (also known as CD276), which is a type I transmembrane protein having four Ig-like extracellular domains. B7-H4 is one of the immune checkpoint proteins expressed on the surface of antigen-presenting cells or cancer cells, and has an inhibitory effect on the functional activation of T cells. The term "B7-H4" includes any variant or isoform of B7-H4 that is naturally expressed by a cell. Antibodies of the invention are capable of cross-reacting with B7-H4 derived from a non-human species. As another option, the antibody may also be specific for human B7-H4 and not show cross-reactivity with other species. B7-H4 or any variant or isoform thereof can be isolated from cells or tissues that naturally express it, or produced by recombinant techniques using techniques commonly used in the art and techniques described herein. Preferably, said anti-B7-H4 antibody targets human B7-H4 with a conventional glycosylation pattern.
"재조합 인간 항체"란 용어는 재조합 방법에 의해 제조되거나, 발현되거나, 생성되거나 단리된 인간 항체, 예를 들어 (1) 인간 면역글로불린 유전자를 발현하는 트랜스제닉 또는 트랜스염색체 동물(예를 들어 마우스)로부터 단리된 항체, 또는 이로부터 제조된 하이브리도마; (2) 항체를 발현하도록 형질전환된 숙주 세포로부터 단리된 항체, 예를 들어 형질감염종; (3) 재조합 인간 항체 라이브러리로부터 단리된 항체; 및 (4) 인간 면역글로불린 유전자 서열을 다른 DNA 서열에 이어맞춤으로써 및 다른 방법에 의해 제조되거나, 발현되거나, 생성되거나 단리된 항체를 포함하고, 관련된 기법 및 방법은 당해 분야에 주지되어 있다. 상기와 같은 재조합 인간 항체는, 생식세포계열 유전자에 의해 암호화된 특정한 인간 생식세포계열 면역글로불린 서열을 이용하지만 항체 성숙 중 발생하는 것들과 같은 후속적인 재배열 및 돌연변이도 포함하는 가변 영역 및 불변 영역을 포함한다.The term "recombinant human antibody" refers to a human antibody prepared, expressed, generated or isolated by recombinant methods, eg, (1) a transgenic or transchromosomal animal (eg, a mouse) expressing a human immunoglobulin gene. an antibody isolated from, or a hybridoma prepared therefrom; (2) an antibody isolated from a host cell transformed to express the antibody, eg, a transfected species; (3) an antibody isolated from a recombinant human antibody library; and (4) antibodies prepared, expressed, generated or isolated by splicing human immunoglobulin gene sequences with other DNA sequences and by other methods, related techniques and methods are well known in the art. Such recombinant human antibodies utilize specific human germline immunoglobulin sequences encoded by germline genes, but contain variable and constant regions that also contain subsequent rearrangements and mutations, such as those that occur during antibody maturation. include
본 발명에서 "쥐 항체"란 용어는 당해 분야의 지식과 기술에 따라 제조된 인간 B7-H4에 대한 단클론 항체이다. 제조 중에, 시험 피실험자는 B7-H4 항원이 주입되고, 이어서 목적하는 서열 또는 기능적 성질을 갖는 항체를 발현하는 하이브리도마가 단리된다. 본 발명의 바람직한 실시태양에서, 쥐 B7-H4 항체 또는 이의 항원-결합 단편은 쥐 κ, λ 쇄 또는 이의 변이체의 경쇄 불변 영역을 추가로 포함하거나, 쥐 IgG1, IgG2, IgG3 또는 IgG4 또는 이의 변이체의 중쇄 불변 영역을 추가로 포함할 수 있다.In the present invention, the term "murine antibody" refers to a monoclonal antibody against human B7-H4 prepared according to the knowledge and technology in the art. During manufacture, test subjects are injected with the B7-H4 antigen, and hybridomas expressing antibodies with the desired sequence or functional properties are then isolated. In a preferred embodiment of the present invention, the murine B7-H4 antibody or antigen-binding fragment thereof further comprises a light chain constant region of a murine κ, λ chain or a variant thereof, or of a murine IgG1, IgG2, IgG3 or IgG4 or variant thereof. It may further comprise a heavy chain constant region.
"인간 항체"란 용어는 인간 생식세포계열 면역글로불린 서열의 가변 및 불변 영역을 갖는 항체를 포함한다. 본 발명의 인간 항체는 인간 생식세포계열 면역글로불린 서열에 의해 암호화되지 않는 아미노산 잔기(예를 들어 시험관내에서 무작위 또는 부위-특이적 돌연변이유발에 의해 또는 생체내에서 체세포 돌연변이에 의해서 도입된 돌연변이)를 포함할 수 있다. 그러나, "인간 항체"란 용어는 또 다른 포유동물 종(예를 들어 마우스)의 생식세포계열로부터 유래된 CDR 서열이 인간 프레임워크 서열상에 접목된 항체(즉 "인간화된 항체")는 포함하지 않는다.The term "human antibody" includes antibodies having variable and constant regions of human germline immunoglobulin sequences. Human antibodies of the invention contain amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). may include However, the term "human antibody" does not include antibodies (ie "humanized antibodies") in which CDR sequences derived from the germline of another mammalian species (eg, mouse) have been grafted onto human framework sequences. does not
"인간화된 항체"(또한 CDR-접목된 항체로서 공지됨)란 용어는 쥐 CDR 서열을 인간 항체 가변 영역의 프레임워크에 접목시킴으로써 생성된 항체를 지칭한다. 상기 항체는 다량의 쥐 단백질 성분을 운반하는 키메라 항체에 의해 유도되는 강한 면역 반응을 극복할 수 있다. 면역원성 감소에 의해 야기되는 활성의 감소를 피하기 위해서, 인간 항체 가변 영역에 최소의 역 돌연변이를 가하여 상기 활성을 유지시킬 수 있다.The term "humanized antibody" (also known as a CDR-grafted antibody) refers to an antibody generated by grafting murine CDR sequences into the framework of a human antibody variable region. Such antibodies are able to overcome the strong immune response induced by chimeric antibodies carrying large amounts of murine protein components. To avoid a decrease in activity caused by reduced immunogenicity, minimal back mutations can be made to the human antibody variable region to maintain this activity.
"키메라 항체"란 용어는 쥐 항체의 가변 영역을 인간 항체의 불변 영역과 융합시킴으로써 형성된 항체이고, 이는 상기 쥐 항체에 의해 유도된 면역 반응을 완화시킬 수 있다. 키메라 항체의 확립은 먼저 쥐 특이적 단클론 항체를 분비하는 하이브리도마를 확립시키고, 이어서 상기 쥐 하이브리도마 세포로부터 가변 영역 유전자를 클로닝하고, 이어서 필요에 따라 상기 인간 항체의 불변 영역 유전자를 클로닝하고, 상기 쥐 가변 영역 유전자와 상기 인간 불변 영역 유전자를 연결하여 키메라 유전자(인간 발현 벡터에 삽입된다)를 형성시키고, 최종적으로 상기 키메라 항체 분자를 진핵생물 산업 시스템 또는 원핵생물 산업 시스템에서 발현시킴을 요한다. 상기 인간 항체 불변 영역은, 바람직하게는 인간 IgG2 또는 IgG4 중쇄 불변 영역을 포함하거나 또는 아미노산 돌연변이 후에 증대된 ADCC(항체-의존적인 세포-매개된 세포독성) 독성을 갖는 IgG1을 사용하는, 인간 IgG1, IgG2, IgG3 또는 IgG4 또는 이들의 변이체의 중쇄 불변 영역으로부터 선택될 수 있다.The term "chimeric antibody" is an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which is capable of ameliorating the immune response induced by the murine antibody. The establishment of a chimeric antibody is first to establish a hybridoma secreting a murine-specific monoclonal antibody, followed by cloning the variable region gene from the murine hybridoma cell, followed by cloning the constant region gene of the human antibody as necessary. , linking the murine variable region gene and the human constant region gene to form a chimeric gene (inserted into a human expression vector), and finally expressing the chimeric antibody molecule in a eukaryotic industrial system or a prokaryotic industrial system. . wherein said human antibody constant region preferably comprises a human IgG2 or IgG4 heavy chain constant region or uses an IgG1 with enhanced ADCC (antibody-dependent cell-mediated cytotoxicity) toxicity after amino acid mutation, human IgG1, heavy chain constant region of IgG2, IgG3 or IgG4 or variants thereof.
"항원-결합 단편"이란 용어는 대개는 모 항체의 항원-결합 영역 또는 가변 영역(예를 들어 하나 이상의 CDR)의 적어도 일부를 포함하는, 항체의 항원-결합 단편 및 항체 유사체를 지칭한다. 상기 항체 단편은 모 항체의 결합 특이성 중 적어도 일부를 보유한다. 일반적으로, 활성을 몰 기준으로 나타내는 경우, 상기 항체 단편은 모 결합 활성의 적어도 10%를 보유한다. 바람직하게는, 상기 항체 단편은 표적에 대한 모 항체의 결합 친화성 중 적어도 20%, 50%, 70%, 80%, 90%, 95% 또는 100% 또는 그 이상을 보유한다. 항원-결합 단편의 예는 비제한적으로 Fab, Fab', F(ab')2, Fv 단편, 선형 항체, 단쇄 항체, 나노바디, 도메인 항체 및 다중특이성 항체를 포함한다. 조작된 항체 변이체는 문헌[Holliger and Hudson (2005) Nat. Biotechnol. 23: 1126-1136]에 리뷰되어 있다.The term "antigen-binding fragment" refers to antigen-binding fragments of an antibody and antibody analogs, usually comprising at least a portion of the antigen-binding region or variable region (eg, one or more CDRs) of a parent antibody. The antibody fragment retains at least some of the binding specificities of the parent antibody. Generally, when activity is expressed on a molar basis, the antibody fragment retains at least 10% of the parental binding activity. Preferably, the antibody fragment retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the binding affinity of the parent antibody for the target. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, linear antibodies, single chain antibodies, Nanobodies, domain antibodies, and multispecific antibodies. Engineered antibody variants are described in Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136].
"Fab 단편"은 하나의 경쇄 및 하나의 중쇄의 CH1 및 가변 영역으로 이루어진다. Fab 분자의 중쇄는 또 다른 중쇄 분자와 다이설파이드 결합을 형성할 수 없다.A “Fab fragment” consists of the CH1 and variable regions of one light chain and one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.
"Fc" 영역은 항체의 CH1 및 CH2 도메인을 포함하는 2개의 중쇄 단편을 포함한다. 상기 2개의 중쇄 단편은 2개 이상의 다이설파이드 결합에 의해서 및 CH3 도메인의 소수성 상호작용을 통해서 함께 유지된다.The “Fc” region comprises two heavy chain fragments comprising the CH1 and CH2 domains of an antibody. The two heavy chain fragments are held together by at least two disulfide bonds and through hydrophobic interactions of the CH3 domain.
"Fab' 단편"은 경쇄, 및 VH 도메인, CH1 도메인, 및 CH1과 CH2 도메인 사이의 영역(따라서 쇄간 다이설파이드 결합이 2개의 Fab' 단편의 2개의 중쇄 사이에 형성될 수 있다)을 포함하여 F(ab')2 분자를 형성한다.A "Fab' fragment" is an F comprising a light chain and a VH domain, a CH1 domain, and a region between the CH1 and CH2 domains (thus, an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments). (ab')2 forms a molecule.
"F(ab')2 단편"은 2개의 경쇄 및 CH1과 CH2 도메인 사이의 불변 영역의 일부를 포함하는(이에 의해 2개의 중쇄 사이에 쇄간 다이설파이드 결합을 형성한다) 2개의 중쇄를 포함한다. 따라서, 상기 F(ab')2 단편은 2개의 중쇄간의 다이설파이드 결합에 의해 함께 유지되는 2개의 Fab' 단편으로 이루어진다.An “F(ab′)2 fragment” comprises two light chains and two heavy chains comprising a portion of the constant region between the CH1 and CH2 domains, thereby forming an interchain disulfide bond between the two heavy chains. Thus, the F(ab')2 fragment consists of two Fab' fragments held together by a disulfide bond between the two heavy chains.
"Fv 영역"은 중쇄와 경쇄 모두로부터의 가변 영역을 포함하지만, 불변 영역은 없다.An “Fv region” includes variable regions from both heavy and light chains, but no constant regions.
"다중특이성 항체"란 용어는 이의 가장 넓은 의미로 사용되고, 다중에피토프 특이성을 갖는 항체를 포함한다. 이러한 다중특이성 항체는 비제한적으로 중쇄 가변 영역(VH) 및 경쇄 가변 영역(VL)을 포함하는 항체(여기서 VH-VL 단위는 다중-에피토프 특이성을 갖는다); 2개 이상의 VL 및 VH 영역(각각의 VH-VL 단위는 상이한 표적 또는 동일한 표적의 상이한 에피토프에 결합한다)을 갖는 항체; 2개 이상의 단일 가변 영역(각각의 단일 가변 영역은 상이한 표적 또는 동일한 표적의 상이한 에피토프에 결합한다)을 갖는 항체; 전장 항체, 항체 단편, 다이아바디, 이중특이성 다이아바디 및 트라이아바디(triabody), 공유적으로 또는 비-공유적으로 함께 연결되는 항체 단편 등을 포함한다.The term "multispecific antibody" is used in its broadest sense and includes antibodies having multiepitope specificity. Such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH-VL unit has multi-epitope specificity; antibodies having two or more VL and VH regions, each VH-VL unit binding to a different target or to a different epitope on the same target; antibodies having two or more single variable regions, each single variable region binding to a different target or to a different epitope on the same target; full length antibodies, antibody fragments, diabodies, bispecific diabodies and triabodies, antibody fragments linked together covalently or non-covalently, and the like.
"단쇄 항체"란 용어는 링커 펩타이드를 통해 항체의 중쇄 가변 영역(VH) 및 경쇄 가변 영역(VL)을 연결함으로써 형성된 단쇄 재조합 단백질이다. 상기 항체는 완전한 항원 결합 부위를 갖는 가장 작은 항체 단편이다.The term "single chain antibody" is a single chain recombinant protein formed by linking the heavy chain variable region (VH) and light chain variable region (VL) of an antibody via a linker peptide. Such antibodies are the smallest antibody fragments with a complete antigen binding site.
"도메인 항체 단편"이란 용어는 오직 중쇄 가변 영역 또는 경쇄 가변 영역만을 포함하는 면역학적 기능을 갖는 면역글로불린 단편이다. 일부의 경우에, 2개 이상의 VH 영역이 펩타이드 링커에 공유적으로 연결되어 2가 도메인 항체 단편을 형성한다. 상기 2가 도메인 항체 단편의 2개의 VH 영역은 동일하거나 상이한 항원을 표적화할 수 있다.The term "domain antibody fragment" is an immunoglobulin fragment with immunological function comprising only a heavy chain variable region or a light chain variable region. In some cases, two or more VH regions are covalently linked to a peptide linker to form a bivalent domain antibody fragment. The two VH regions of the bivalent domain antibody fragment may target the same or different antigens.
본 발명에서 "B7-H4에의 결합"이란 용어는 인간 B7-H4와 상호작용하는 능력을 지칭한다. 본 발명의 "항원-결합 부위"란 용어는, 항원상에 산재되고 본 발명의 항체 또는 항원-결합 단편에 의해 인식되는 3차원 부위를 지칭한다.As used herein, the term "binding to B7-H4" refers to the ability to interact with human B7-H4. The term "antigen-binding site" of the present invention refers to a three-dimensional site interspersed on an antigen and recognized by an antibody or antigen-binding fragment of the present invention.
본 발명에 사용되는 "특이적으로 결합하다" 및 "선택적으로 결합하다"란 용어는 미리결정된 항원상의 에피토프에 대한 항체의 결합을 지칭한다. 일반적으로, 재조합 인간 B7-H4가 분석물로서 사용되고 항체가 리간드로서 사용되는 경우, 장비에서 표면 플라스몬 공명(SPR) 기술에 의해 측정될 때, 상기 항체는 상기 미리결정된 항원에 약 10-7 M 미만 또는 심지어 이보다 작은 평형 해리 상수(KD)로 결합하고, 상기 미리결정된 항원에 대한 이의 결합 친화성은 비-특이성 항원(상기 미리결정된 항원 또는 밀접하게 관련된 항원 이외의, 예를 들어 BSA 등)에 대한 이의 결합 친화성의 적어도 2배이다. "...항원을 인식하는 항체"란 용어는 본원에서 "...에 특이적으로 결합하는 항체"란 용어와 호환가능하게 사용될 수 있다.As used herein, the terms “specifically binds” and “selectively binds” refer to the binding of an antibody to an epitope on a predetermined antigen. Generally, when recombinant human B7-H4 is used as an analyte and an antibody is used as a ligand, the antibody binds to the predetermined antigen at about 10 -7 M, as measured by surface plasmon resonance (SPR) technology in the instrument. binds with an equilibrium dissociation constant (KD) that is less than or even less than this, and its binding affinity for said predetermined antigen is for a non-specific antigen (other than said predetermined antigen or closely related antigen, e.g., BSA, etc.) at least twice its binding affinity. The term "antibody recognizing antigen" may be used herein interchangeably with the term "antibody that specifically binds to...".
"교차-반응성"이란 용어는 상이한 종들로부터의 B7-H4에 결합하는 본 발명의 항체의 능력을 지칭한다. 예를 들어, 인간 B7-H4에 결합하는 본 발명의 항체는 또한 또 다른 종의 B7-H4에도 결합할 수 있다. 교차-반응성을, 결합 분석(예를 들어 SPR 및 ELISA)에서 정제된 항원과의 특이적인 반응성을 검출하거나, B7-H4를 생리학적으로 발현하는 세포와의 결합 또는 기능적 상호작용에 의해 측정한다. 교차-반응성의 측정 방법은 본원에 기재된 바와 같은 표준 결합 분석, 예를 들어 표면 플라스몬 공명(SPR) 분석 또는 유식 세포측정을 포함한다.The term “cross-reactivity” refers to the ability of an antibody of the invention to bind B7-H4 from different species. For example, an antibody of the invention that binds to human B7-H4 may also bind to B7-H4 of another species. Cross-reactivity is measured by detecting specific reactivity with purified antigen in binding assays (eg SPR and ELISA), or by binding or functional interaction with cells physiologically expressing B7-H4. Methods for determining cross-reactivity include standard binding assays as described herein, such as surface plasmon resonance (SPR) assays or flow cytometry.
"억제" 또는 "차단"이란 용어는 호환가능하게 사용될 수 있고 부분적인 및 완전한 억제/차단을 모두 포함한다. 리간드의 억제/차단은 바람직하게는 리간드 결합이 억제나 차단 없이 발생하는 경우 존재하는 통상적인 수준 또는 유형의 활성을 감소시키거나 변경시킨다. 억제 및 차단은 또한 항-B7-H4 항체와 접촉하지 않는 리간드의 결합 친화성에 비해, 항-B7-H4 항체와 접촉하는 경우의 리간드의 결합 친화성의 임의의 측정가능한 감소를 포함하고자 한다.The terms “inhibition” or “blocking” may be used interchangeably and include both partial and complete inhibition/blocking. Inhibition/blocking of the ligand preferably reduces or alters the level or type of activity normally present if ligand binding occurs without inhibition or blocking. Inhibition and blocking are also intended to include any measurable decrease in the binding affinity of a ligand when contacted with an anti-B7-H4 antibody compared to the binding affinity of a ligand not contacted with the anti-B7-H4 antibody.
"성장의 억제"(예를 들어 세포를 언급하는 경우)란 용어는 세포 성장의 임의의 측정가능한 감소를 포함하고자 한다.The term "inhibition of growth" (eg, when referring to cells) is intended to include any measurable decrease in cell growth.
"유도면역반응" 및 "증대된 면역반응"이란 용어는 호환가능하게 사용될 수 있고 특정 항원에 의한 자극에 대한 면역 반응(즉 수동 또는 적응)을 지칭한다. "CDC 또는 ADCC의 유도"란 표현에 사용되는 "유도하다"란 용어는 특정한 직접적인 세포사멸 기전을 자극함을 지칭한다.The terms "induced immune response" and "enhanced immune response" are used interchangeably and refer to an immune response (ie, passive or adaptive) to stimulation by a particular antigen. The term "induce" as used in the expression "induction of CDC or ADCC" refers to stimulating a particular direct mechanism of apoptosis.
본 발명에서 "ADCC", 즉 항체-의존적인 세포-매개된 세포독성은, Fc 수용체를 발현하는 세포가 항체의 Fc 분절을 인식함으로써 상기 항체로 코팅된 표적 세포를 직접 사멸시킴을 의미한다. 항체의 ADCC 효과 기능은 IgG의 Fc 분절을 변형시킴으로써 증대되거나, 감소되거나 또는 제거될 수 있다. 상기 변형은 항체의 중쇄 불변 영역의 돌연변이를 지칭한다.In the present invention, "ADCC", that is, antibody-dependent cell-mediated cytotoxicity, means that cells expressing Fc receptors directly kill target cells coated with the antibody by recognizing the Fc fragment of the antibody. The ADCC effector function of the antibody can be enhanced, reduced or abrogated by modifying the Fc segment of IgG. Such modifications refer to mutations in the heavy chain constant region of an antibody.
항체 및 항원-결합 단편의 생성 및 정제 방법은 주지되어 있고, 종래 기술, 예를 들어 문헌[Antibodies: A Laboratory Manual, Cold Spring Harbor, chapters 5-8 and 15]에서 찾을 수 있다. 예를 들어, 마우스를 인간 B7-H4 또는 이의 단편으로 면역화할 수 있고, 수득된 항체를 재생 및 복원시킬 수 있고, 통상적인 방법을 사용하여 아미노산 서열분석을 수행할 수 있다. 항원-결합 단편을 또한 통상적인 방법을 사용하여 제조할 수 있다. 본 발명의 항체 또는 항원-결합 단편을 유전자 조작하여 하나 이상의 인간 FR 영역을 비-인간 CDR 영역상에 도입시킨다. 인간 FR 생식세포계열 서열을 ImmunoGeneTics(IMGT) 웹사이트 http://imgt.cines.fr로부터, 또는 문헌[Immunoglobulin FactsBook, 2001ISBN012441351]으로부터 획득할 수 있다.Methods for the production and purification of antibodies and antigen-binding fragments are well known and can be found in the prior art, for example, in Antibodies: A Laboratory Manual, Cold Spring Harbor, chapters 5-8 and 15. For example, mice can be immunized with human B7-H4 or a fragment thereof, the obtained antibody can be regenerated and restored, and amino acid sequencing can be performed using conventional methods. Antigen-binding fragments can also be prepared using conventional methods. Antibodies or antigen-binding fragments of the invention are genetically engineered to introduce one or more human FR regions onto non-human CDR regions. Human FR germline sequences can be obtained from the ImmunoGeneTics (IMGT) website at http://imgt.cines.fr, or from Immunoglobulin FactsBook, 2001ISBN012441351.
본 발명의 조작된 항체 또는 항원-결합 단편을 통상적인 방법에 의해 제조하고 정제할 수 있다. 상응하는 항체의 cDNA 서열을 클로닝하고 GS 발현 벡터에 재조합할 수 있다. 재조합 면역글로불린 발현 벡터는 CHO 세포를 안정하게 형질감염시킬 수 있다. 보다 권장되는 선행 기술로서, 포유동물 발현 시스템이, 특히 Fc 영역의 고도로 보존된 N-말단에서 항체의 글리코실화를 유도할 수 있다. 인간 항원에 특이적으로 결합하는 항체를 발현시킴으로써 안정한 클론을 수득한다. 양성 클론을 생물반응기의 무혈청 배지에서 확대시켜 항체를 생성시킨다. 항체가 분비되는 배양 배지를 통상적인 기법에 의해 정제하고 수집할 수 있다. 항체를 통상적인 방법에 의해 여과하고 농축시킬 수 있다. 용해성 혼합물 및 다량체를 또한 통상적인 방법, 예를 들어 분자체 및 이온 교환에 의해 제거할 수 있다. 생성되는 생성물은 즉시, 예를 들어 -70℃에서 동결시키거나 또는 동결건조시킬 필요가 있다.The engineered antibody or antigen-binding fragment of the present invention can be prepared and purified by conventional methods. The cDNA sequence of the corresponding antibody can be cloned and recombined into a GS expression vector. Recombinant immunoglobulin expression vectors can stably transfect CHO cells. As a more recommended prior art, mammalian expression systems can induce glycosylation of antibodies, particularly at the highly conserved N-terminus of the Fc region. Stable clones are obtained by expressing an antibody that specifically binds to a human antigen. Positive clones are expanded in serum-free medium in a bioreactor to generate antibodies. The culture medium in which the antibody is secreted can be purified and collected by conventional techniques. The antibody can be filtered and concentrated by conventional methods. Soluble mixtures and multimers can also be removed by conventional methods, for example molecular sieves and ion exchange. The resulting product needs to be frozen or lyophilized immediately, for example at -70°C.
본 발명의 항체는 단클론 항체를 지칭한다. 본 발명에 기재된 단클론 항체(mAb)는 단일 클로닝된 세포주로부터 수득된 항체를 지칭하고, 상기 세포주는 비제한적으로 진핵생물, 원핵생물 또는 파지 클로닝된 세포주이다. 단클론 항체 또는 항원-결합 단편을, 예를 들어 하이브리도마 기술, 재조합 기술, 파지 디스플레이 기술, 합성 기술(예를 들어 CDR-접목) 또는 다른 기존의 기술을 사용하여 재조합에 의해 수득할 수 있다.Antibodies of the invention refer to monoclonal antibodies. A monoclonal antibody (mAb) as described herein refers to an antibody obtained from a single cloned cell line, said cell line being, but not limited to, a eukaryotic, prokaryotic or phage cloned cell line. Monoclonal antibodies or antigen-binding fragments can be obtained recombinantly, for example, using hybridoma techniques, recombinant techniques, phage display techniques, synthetic techniques (eg CDR-grafting) or other conventional techniques.
"투여하는" 및 "치료하는"은 동물, 인간, 실험 대상자, 세포, 조직, 기관 또는 생물학적 유체에 적용될 때 외인성 약제, 치료제, 진단제 또는 조성물을 상기 동물, 인간, 피실험자, 세포, 조직, 기관 또는 생물학적 유체와 접촉시킴을 지칭한다. "투여하는" 및 "치료하는"은 예를 들어 치료, 약동학, 진단, 연구 및 실험 방법을 지칭할 수 있다. 세포를 치료함은 시약을 상기 세포와 접촉시킴, 및 시약을 유체와 접촉시킴을 포함하고, 여기서 상기 유체는 세포와 접촉하고 있다. "투여하는" 및 "치료하는"은 또한 예를 들어 세포를 시약, 진단제, 결합 조성물로, 또는 또 다른 유형의 세포로 시험관내에서 및 생체외에서 처리함을 의미한다. "치료하는"은 인간, 수의과 또는 연구 피실험자에 적용될 때 치료학적 치료, 예방 또는 예방학적 수단, 연구 및 진단 적용을 지칭한다."Administering" and "treating" refer to an exogenous agent, therapeutic agent, diagnostic agent, or composition when applied to an animal, human, test subject, cell, tissue, organ, or biological fluid, said animal, human, subject, cell, tissue, organ. or contact with a biological fluid. “Administering” and “treating” may refer to, for example, treatment, pharmacokinetics, diagnostics, research and laboratory methods. Treating a cell comprises contacting a reagent with the cell, and contacting a reagent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating a cell in vitro and ex vivo, for example with a reagent, diagnostic agent, binding composition, or another type of cell. "Treating" refers to therapeutic treatment, prophylactic or prophylactic means, research and diagnostic applications when applied to human, veterinary or research subjects.
"치료"는 내부 또는 외부 치료제, 예를 들어 본 발명의 결합 화합물 중 어느 하나를 포함하는 조성물을, 상기 치료제가 치료학적 효과를 갖는 것으로 공지된 하나 이상의 질병 증상이 있는 환자에게 투여함을 지칭한다. 일반적으로, 상기 치료제를, 치료된 피실험자 또는 집단에서 하나 이상의 질병 증상을 완화시키고, 상기와 같은 증상의 퇴행을 유도하거나 또는 상기와 같은 증상의 임의의 임상적으로 측정가능한 정도로의 발달을 억제하기에 유효한 양으로 제공한다. 임의의 특정한 질병 증상을 완화시키기에 유효한 치료제의 양(또한 "치료 유효량"으로서 지칭된다)은 다양한 인자, 예를 들어 환자의 질병 상태, 연령 및 체중, 및 환자에서 목적하는 치료 효과를 생성시키는 약물의 능력에 따라 변할 수 있다. 질병 증상이 완화되었는지의 여부는 상기 증상의 중증도 또는 진행의 평가를 위해 의사나 다른 의료 전문가에 의해 통상적으로 사용되는 임의의 임상적 시험 방법에 의해 평가될 수 있다. 본 발명의 실시태양(예를 들어 치료 방법 또는 생성물)이 각각의 관심 질병 증상을 완화시키는데 유효하지 않을 수도 있지만, 이들 실시태양은 상기 관심 질병 증상을 당해 분야에 공지된 임의의 통계학적 검정, 예를 들어 스튜던트 t-검정, 카이-제곱 검정, 만과 휘트니의 U 검정, 크루스칼-월리스 검정(H 검정), 존키어-터프스트라 검정 및 윌콕슨 검정에 의해 측정시, 통계학적으로 유의미한 수의 환자에서 상기 관심 질병 증상을 감소시켜야 한다."Treatment" refers to administration of a composition comprising either an internal or external therapeutic agent, e.g., a binding compound of the present invention, to a patient having one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. . In general, the therapeutic agent is administered to alleviate one or more symptoms of a disease, induce regression of such symptoms, or inhibit the development of any clinically measurable degree of such symptoms in the treated subject or population. provided in an effective amount. The amount of a therapeutic agent effective to ameliorate any particular disease symptom (also referred to as a "therapeutically effective amount") depends on a variety of factors, including the disease state, age and weight of the patient, and the drug that produces the desired therapeutic effect in the patient. may vary depending on the ability of Whether a disease symptom has been alleviated can be assessed by any clinical test method commonly used by a physician or other medical professional for evaluation of the severity or progression of the symptom. Although embodiments of the present invention (eg, methods or products of treatment) may not be effective in alleviating each symptom of a disease of interest, these embodiments can be used to evaluate the symptom of a disease of interest by any statistical assay known in the art, such as A statistically significant number of patients as measured by, for example, Student's t-test, chi-square test, Mann and Whitney's U test, Kruskal-Wallis test (H test), Johnkier-Tufstra test, and Wilcoxon test should reduce the symptoms of the disease of interest.
명세서 및 청구범위 전체를 통해 사용되는 "...로 필수적으로 이루어진"이란 용어 또는 이의 변형은 기재된 모든 요소 또는 요소 군을 포함하고, 주어진 투여 섭생, 방법 또는 조성물의 기본적인 또는 새로운 성질을 그다지 변화시키지 않는, 사실상 기재된 요소와 유사하거나 상이한 다른 요소를 임의로 포함함을 의미한다. 비제한적인 예로서, 언급된 아미노산 서열로 필수적으로 이루어진 결합 화합물은 또한 상기 결합 화합물의 성질에 그다지 영향을 미치지 않는 하나 이상의 아미노산을 포함할 수 있다.As used throughout the specification and claims, the term "consisting essentially of, or variations thereof, includes all described elements or groups of elements and does not significantly alter the basic or novel properties of a given administration regimen, method or composition. not, in fact, meant to optionally include other elements similar or different from those described. As a non-limiting example, a binding compound consisting essentially of a recited amino acid sequence may also comprise one or more amino acids that do not significantly affect the properties of the binding compound.
본 발명의 몇몇 대상에 적용되는 "천연"이란 용어는 상기 대상이 자연에서 발견될 수 있다는 사실을 지칭한다. 예를 들어, 폴리펩타이드 서열 또는 폴리뉴클레오타이드 서열은 유기체(바이러스 포함) 중에 존재하고 자연 공급원으로부터 단리되고 실험실에서 인공적으로 의도적으로 변형되지 않은 경우 천연으로서 간주된다.The term “natural” as applied to some objects of the present invention refers to the fact that such objects can be found in nature. For example, a polypeptide sequence or polynucleotide sequence is considered natural if it exists in an organism (including viruses), is isolated from a natural source, and has not been intentionally modified artificially in the laboratory.
"유효량"은 의학적 상태의 증상 또는 상태를 개선시키거나 예방하기에 충분한 양을 포함한다. 상기 유효량은 또한 진단을 허용하거나 용이하게 하기에 충분한 양을 지칭한다. 특정 환자 또는 수의학 피실험자에 대한 유효량은 하기의 인자에 따라 변할 수 있다: 예를 들어 치료되는 상태, 환자의 일반적인 건강 상태, 약물 투여 방법, 경로 및 용량, 및 부작용의 중증도. 유효량은 현저한 부작용 또는 독성 효과를 피하는 최대 용량 또는 용량 섭생일 수 있다.An “effective amount” includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. Said effective amount also refers to an amount sufficient to permit or facilitate diagnosis. An effective amount for a particular patient or veterinary subject may vary depending on the following factors: for example, the condition being treated, the patient's general health, the method, route and dosage, and severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
"외인성"은 배경에 따른 유기체, 세포 또는 인체 밖에서 생성된 물질을 지칭한다. "내인성"은 배경에 따른 세포, 유기체 또는 인체 내부에서 생성된 물질을 지칭한다.“Exogenous” refers to an organism, cell, or material produced outside the body according to the background. "Endogenous" refers to a cell, organism, or material produced inside the human body depending on the background.
"상동성"은 2개의 폴리뉴클레오티드 서열간 또는 2개의 폴리펩타이드간의 서열 유사성을 지칭한다. 정렬된 2개 서열 중의 위치가 동일한 염기 또는 아미노산 단량체 서브유닛에 의해 점유되는 경우, 예를 들어 2개의 DNA 분자의 각 위치가 아데닌에 의해 점유되는 경우, 상기 분자는 상기 위치에서 상동성인 것으로 간주된다. 2개 서열간의 상동성 백분율은 상기 두 서열에 의해 공유된 합치되거나 상동성인 위치의 수를 정렬된 위치의 수로 나누어 100%를 곱한 함수이다. 예를 들어, 최적의 서열 정렬에서, 2개 서열의 10개 위치 중 6개가 합치되거나 상동성인 경우, 상기 두 서열은 60%의 상동성이다. 일반적으로, 상기 정렬은 2개 서열을 최대의 상동성 백분율을 획득하도록 정렬하는 경우 이루어진다."Homology" refers to sequence similarity between two polynucleotide sequences or between two polypeptides. A molecule is considered homologous at that position if a position in two aligned sequences is occupied by the same base or amino acid monomer subunit, for example, if each position in two DNA molecules is occupied by an adenine. . The percent homology between two sequences is a function of the number of coincident or homologous positions shared by the two sequences divided by the number of aligned positions multiplied by 100%. For example, in an optimal sequence alignment, if 6 out of 10 positions of the two sequences are congruent or homologous, then the two sequences are 60% homologous. In general, such alignments are made when the two sequences are aligned to obtain the greatest percentage of homology.
본원에 사용된 "세포", "세포주" 및 "세포 배양물"이란 표현은 호환가능하게 사용될 수 있고, 상기와 같은 명칭은 모두 이들의 자손을 포함한다. 따라서, "형질전환체" 및 "형질전환된 세포"란 단어는 1차 시험 세포, 및 계대수에 관계 없이 그로부터 배양된 배양물을 포함한다. 또한, 의도적인 또는 의도적이지 않은 돌연변이로 인해, 모든 자손이 DNA 함량의 면에서 정확하게 동일하지 않을 수 있음을 알아야 한다. 원래의 형질전환된 세포에서 선별된 경우와 동일한 기능 또는 생물학적 활성을 갖는 돌연변이 자손이 포함된다. 상이한 명칭이 언급될 때 이는 문맥을 통해 명확하게 이해될 수 있다.As used herein, the expressions "cell", "cell line" and "cell culture" may be used interchangeably, and all such designations include their progeny. Accordingly, the words "transformants" and "transformed cells" include primary test cells, and cultures cultured therefrom, regardless of the number of passages. It should also be noted that, due to intentional or unintentional mutation, not all progeny may be exactly identical in terms of DNA content. Mutant progeny that have the same function or biological activity as were selected for in the originally transformed cell are included. When different names are referred to, they may be clearly understood from the context.
"임의의" 또는 "임의로"는 "임의의" 또는 "임의로"라는 단어 뒤에 오는 사건 또는 상황이 발생할 수 있지만 발생할 필요는 없고 설명에는 상기 사건 또는 상황이 발생하거나 발생하지 않는 경우가 포함됨을 의미한다. 예를 들어, "임의로 1 내지 3개의 항체 중쇄 가변 영역을 포함하는"은 특정 서열의 항체 중쇄 가변 영역이 존재할 수 있지만 존재할 필요는 없음을 의미한다. "optionally" or "optionally" means that the event or circumstance following the word "optionally" or "optionally" may, but need not, occur, and that the description includes instances in which said event or circumstance occurs or does not occur . For example, "optionally comprising 1 to 3 antibody heavy chain variable regions" means that an antibody heavy chain variable region of a particular sequence may, but need not, be present.
"약학 조성물"은 본원에 기재된 화합물 중 하나 이상, 또는 이의 생리학적/약학적으로 허용가능한 염 또는 전구약물, 및 다른 화학적 성분뿐만 아니라 다른 성분, 예를 들어 생리학적/약학적으로 허용가능한 담체 및 부형제를 함유하는 혼합물을 의미한다. 상기 약학 조성물의 목적은 유기체에의 약물 투여를 촉진하고, 활성 성분의 흡수를 촉진하고 이에 의해 생물학적 활성을 발휘하기 위한 것이다. 통상적인 약학 조성물의 제조는 중국 약전에 기재되어 있다.A “pharmaceutical composition” refers to one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components as well as other components such as a physiologically/pharmaceutically acceptable carrier and mixtures containing excipients. The purpose of the pharmaceutical composition is to facilitate drug administration to an organism, promote absorption of an active ingredient and thereby exert biological activity. The preparation of conventional pharmaceutical compositions is described in the Chinese Pharmacopoeia.
"약학적으로 허용가능한 염"은 포유동물에 사용하기에 안전하고 유효하고 목적하는 생물학적 활성을 갖는, 본 발명의 항체-약물 접합체의 염을 지칭한다. 본 발명의 항체-약물 접합체는 하나 이상의 아미노기를 포함하고, 따라서 상기 접합체는 산과 염을 형성할 수 있다. 약학적으로 허용가능한 염의 비제한적인 예는 하이드로클로라이드, 하이드로브로마이드, 하이드로요오다이드, 설페이트, 수소 설페이트, 시트레이트, 아세테이트, 숙시네이트, 아스코르베이트, 옥살레이트, 나이트레이트, 소르베이트, 수소 포스페이트, 이수소 포스페이트, 살리실레이트, 수소 시트레이트, 타르트레이트, 말리에이트, 퓨마레이트, 포르메이트, 벤조에이트, 메탄설포네이트, 에탄설포네이트, 벤젠설포네이트 및 p-톨루엔설포네이트를 포함한다."Pharmaceutically acceptable salt" refers to a salt of the antibody-drug conjugate of the present invention that is safe and effective for use in mammals and has the desired biological activity. The antibody-drug conjugates of the present invention contain one or more amino groups, and thus the conjugates are capable of forming salts with acids. Non-limiting examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate , dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.
"용매화물"은 본 발명의 항체-약물 접합체 화합물 및 하나 이상의 용매 분자에 의해 형성된 약학적으로 허용가능한 용매화물을 지칭한다. 용매 분자의 비제한적인 예는 수, 에탄올, 아세토나이트릴, 아이소프로판올 및 에틸 아세테이트를 포함한다.“Solvate” refers to a pharmaceutically acceptable solvate formed by an antibody-drug conjugate compound of the invention and one or more solvent molecules. Non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol and ethyl acetate.
"세포독성 약물"은 본 발명에서 사용될 때, 세포의 기능을 억제하고/하거나 세포사 또는 파괴를 일으키는 물질을 지칭한다."Cytotoxic drug", as used herein, refers to a substance that inhibits the function of a cell and/or causes cell death or destruction.
"튜불린 억제제"는 튜불린의 중합을 억제하거나 튜블린의 응집을 촉진함으로써 세포 유사분열의 과정을 방해하여 항-종양 효과를 발휘는 화합물의 한 부류를 지칭한다. 이의 비제한적인 예는 메이탄시노이드, 칼케아미신, 탁산, 빈크리스틴, 콜히친, 돌라스타틴/아우리스타틴/모노메틸 아우리스타틴 E(MMAE)/모노메틸 아우리스타틴 F(MMAF)를 포함한다."Tubulin inhibitor" refers to a class of compounds that exert anti-tumor effects by inhibiting the polymerization of tubulin or promoting aggregation of tubulin, thereby interfering with the process of cell mitosis. Non-limiting examples thereof include maytansinoids, calcheamicin, taxane, vincristine, colchicine, dolastatin/auristatin/monomethyl auristatin E (MMAE)/monomethyl auristatin F (MMAF) do.
"링커"는 항체를 약물의 공유 결합 또는 원자쇄에 공유적으로 부착시키는 화학적 부분을 지칭한다. 링커의 비제한적인 예는 아릴렌, 헤테로아릴렌, PEG, 폴리메틸렌옥시, 숙시네이트, 숙신아미드, 다이글리콜레이트, 말로네이트 및 카프로아미드를 포함한다.“Linker” refers to a chemical moiety that covalently attaches an antibody to a covalent bond or atomic chain of a drug. Non-limiting examples of linkers include arylene, heteroarylene, PEG, polymethyleneoxy, succinate, succinamide, diglycolate, malonate, and caproamide.
"약물 부하"(DAR)는 y로 나타내는데, 이는 화학식 A에서 항체당 세포독성 약물의 평균수이다. 본 발명에서 약물 부하의 범위는 항체당 1-20 세포독성 약물(D)일 수 있다. 화학식 A의 항체-약물 접합체는 특정 범위(1-20)의 세포독성 약물에 접합된 항체의 집합체이다. 커플링 반응으로부터의 항체-약물 접합체 중의 약물 부하(DAR)는 통상적인 수단, 예를 들어 질량 분광분석, HPLC 및 ELISA에 의해 특성화될 수 있다. 이러한 수단에 의해, y 값에 대한 항체-약물 접합체의 정량적인 분포를 측정할 수 있다.“Drug load” (DAR) is denoted by y, which is the average number of cytotoxic drugs per antibody in Formula A. In the present invention, the range of drug loading may be 1-20 cytotoxic drugs (D) per antibody. An antibody-drug conjugate of formula (A) is a collection of antibodies conjugated to a specific range (1-20) of a cytotoxic drug. The drug load (DAR) in the antibody-drug conjugate from the coupling reaction can be characterized by conventional means such as mass spectrometry, HPLC and ELISA. By this means, it is possible to determine the quantitative distribution of the antibody-drug conjugate with respect to the y value.
2. 약어2. Abbreviations
MC = 6-말레이미도헥사노일MC = 6-maleimidohexanoyl
VC = 발린-시트룰린VC = valine-citrulline
PAB = p-아미노벤질옥시카보닐PAB = p-aminobenzyloxycarbonyl
MMAE = 모노메틸 아우리스타틴 E(MW 718)MMAE = monomethyl auristatin E (MW 718)
MMAF = 분자(MW 731.5)의 C-말단에 페닐알라닌을 갖는, 모노메틸 아우리스타틴 E의 변이체MMAF = variant of monomethyl auristatin E with phenylalanine at the C-terminus of the molecule (MW 731.5)
본 발명의 추가의 기재를 위해 하기에 실시예를 포함시키지만, 이들 실시예는 본 발명의 범위를 제한하지 않는다. 본 발명의 실시예에서 명시되지 않은 조건을 갖는 실험 방법은 일반적으로 통상적인 조건, 예를 들어 문헌[Antibodies: A Laboratory Manual and Molecular Cloning: A Laboratory Manual, Cold Spring Harbor]을 따르거나; 원료 물질 또는 원자재 제조사에 의해 권장되는 조건에 따른다. 명시되지 않은 출처를 갖는 시약은 시중에서 구입되는 통상적인 시약이다.Examples are included below for further description of the invention, but these examples do not limit the scope of the invention. Experimental methods having conditions not specified in the examples of the present invention generally follow conventional conditions, for example, Antibodies: A Laboratory Manual and Molecular Cloning: A Laboratory Manual, Cold Spring Harbor; Follow the conditions recommended by the raw material or raw material manufacturer. Reagents with unspecified sources are commercially available conventional reagents.
실시예 1: 항원 제조 및 안정한 세포주 구성Example 1: Antigen Preparation and Stable Cell Line Construction
his-태그된 인간 B7-H4(huB7-H4-His)를 암호화하는 서열 및 Fc-태그된 인간 B7-H4(huB7-H4-Fc)를 암호화하는 서열을 CRO의 인티그레이티드 DNA 테크놀로지(IDT)(Integrated DNA Technology (IDT))에 의해 합성하고(상기 B7-H4 재조합 단백질의 주형 서열은 모두 본 발명에 의해 설계되었다) 각각 pTT5 벡터(바이오벡터(Biovector))내에 클로닝하였다. 재조합 B7-H4 단백질을 293T 세포에서 발현시킨 후에, 하기의 실험 방법에 의해 정제시키고, 정제된 단백질을 실시예의 다음 실험들에 사용할 수 있었다.The sequence encoding his-tagged human B7-H4 (huB7-H4-His) and the sequence encoding Fc-tagged human B7-H4 (huB7-H4-Fc) were obtained from CRO's Integrated DNA Technology (IDT) (Integrated DNA Technology (IDT)) and (the template sequence of the B7-H4 recombinant protein was all designed by the present invention) and each cloned into a pTT5 vector (Biovector). After the recombinant B7-H4 protein was expressed in 293T cells, it was purified by the following experimental method, and the purified protein could be used in the following experiments of Examples.
huB7-H4-His의 서열:The sequence of huB7-H4-His:
MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKADYKDDDDKGSHHHHHHHH 서열번호 1MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKADYKDDDDKGSHHHHHHHH SEQ ID NO: 1
huB7-H4-Fc의 서열:Sequence of huB7-H4-Fc:
FGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKAGSGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 서열번호 2FGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIENDIAKATGDIKVTESEIKRRSHLQLLNSKAGSGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 2
huB7-H4-His의 정제 단계:Purification steps of huB7-H4-His:
HEK293 세포 발현 상등액 샘플을 고속으로 원심분리시켜 불순물을 제거하였다. 완충제를 PBS에 대해 교체하고 이미다졸을 5 mM의 최종 농도로 가하였다. 니켈 컬럼을 5 mM 이미다졸을 함유하는 PBS 용액으로 평형화하고 컬럼 부피의 2 내지 5배로 세척하였다. 교체 후에 수득된 상등액 샘플을 컬럼상에 로딩하였다. 컬럼을 A280 판독이 기준선으로 떨어질 때까지, 5 mM 이미다졸을 함유하는 PBS 용액으로 세정하였다. 이어서 크로마토그래피 컬럼을 PBS+10 mM 이미다졸로 세정하여 비-특이적으로 결합된 단백질 불순물을 제거하고, 용출물을 수집하였다. 표적 단백질을 300 mM 이미다졸을 함유하는 PBS 용액으로 용출시키고, 용출 피크를 수집하였다. 수집된 용출물을 이온 교환(SP 컬럼)에 의해 추가로 정제하였다. A 용액 제조: 0.01 M PB, pH 8.0. B 용액 제조: A 용액 + 1 M NaCl. 먼저, 용출된 표적 단백질을 갖는 이미다졸의 PBS 용액을 용액 A에 대해 교체하고, SP 컬럼을 용액 A를 사용하여 평형화하고 샘플을 로딩하였다. 용액 B의 농도 구배는 0 내지 100%였다. 샘플을 컬럼 부피의 10배로 용출시키고, 각 용출 피크를 수집하였다. 수득된 단백질은 전기영동, 펩타이드 지도 및 액체 크로마토그래피-질량 분광분석(LC-MS)에 의해 정확한 것으로서 확인되었고, 이어서 사용을 위해 분액하였다.HEK293 cell expression supernatant samples were centrifuged at high speed to remove impurities. The buffer was replaced against PBS and imidazole was added to a final concentration of 5 mM. The nickel column was equilibrated with a PBS solution containing 5 mM imidazole and washed with 2-5 times the column volume. A sample of the supernatant obtained after replacement was loaded onto the column. The column was washed with a PBS solution containing 5 mM imidazole until the A280 reading fell to baseline. The chromatography column was then washed with PBS+10 mM imidazole to remove non-specifically bound protein impurities, and the eluate was collected. The target protein was eluted with a PBS solution containing 300 mM imidazole, and the elution peak was collected. The collected eluate was further purified by ion exchange (SP column). Preparation of solution A: 0.01 M PB, pH 8.0. Prepare solution B: solution A + 1 M NaCl. First, the PBS solution of imidazole with the eluted target protein was replaced for solution A, the SP column was equilibrated using solution A and the sample was loaded. The concentration gradient of solution B was 0-100%. Samples were eluted at 10 times the column volume and each elution peak was collected. The obtained protein was confirmed as correct by electrophoresis, peptide mapping and liquid chromatography-mass spectrometry (LC-MS), and then aliquoted for use.
huB7-H4-Fc의 정제 단계:Purification steps of huB7-H4-Fc:
HEK293 세포 발현 상등액 샘플을 고속으로 원심분리시켜 불순물을 제거하였다. 완충제를 PBS에 대해 교체하였다. 단백질 A 친화성 컬럼을 10 mM PBS 완충제로 평형화하고 컬럼 부피의 2-5배로 세척하였다. 교체 후에 수득된 상등액 샘플을 컬럼상에 로딩하였다. 컬럼을 A280 판독이 기준선으로 떨어질 때까지 컬럼 부피의 25배 완충제로 세척하였다. 표적 단백질을 pH 3.5의 0.8% 아세테이트 완충제로 용출시키고 용출 피크를 수집하였다. 분액 후에, 1 M 트리스-Cl pH 8.0 완충제를 중화를 위해 즉시 첨가하였다. 이어서 용액을 밀리포어(Millipore)의 아미코(Amico)-15 필터 컬럼을 사용하여 PBS pH 6.9에 대해 교체하였다. 수득된 단백질은 전기영동, 펩타이드 지도 및 액체 크로마토그래피-질량 분광분석(LC-MS)에 의해 확인되었고, 이어서 사용을 위해 분액하였다.HEK293 cell expression supernatant samples were centrifuged at high speed to remove impurities. The buffer was replaced against PBS. The Protein A affinity column was equilibrated with 10 mM PBS buffer and washed with 2-5 times the column volume. A sample of the supernatant obtained after replacement was loaded onto the column. The column was washed with 25 times the column volume of buffer until the A280 reading fell to baseline. The target protein was eluted with 0.8% acetate buffer at pH 3.5 and the elution peak was collected. After aliquots, 1 M Tris-Cl pH 8.0 buffer was added immediately for neutralization. The solution was then exchanged against PBS pH 6.9 using an Amico-15 filter column from Millipore. The obtained protein was confirmed by electrophoresis, peptide mapping and liquid chromatography-mass spectrometry (LC-MS), and then aliquoted for use.
안정한 CHO-S 세포 풀(pool)의 구성:Composition of the stable CHO-S cell pool:
인간 또는 키노몰구스 원숭이 B7-H4 단백질(huB7-H4 또는 cyB7-H4)을 암호화하는 전장 서열을 인티그레이티드 DNA 테크놀로지(IDT)에 의해 합성하고(상기 B7-H4 재조합 단백질의 주형 서열은 모두 본 발명에 의해 설계되었다) 각각 변형된 pcDNA3.1 벡터, pcDNA3.1/퓨로(인비트로젠(Invitrogen) #V79020)내에 클로닝하였다. CHO-S(ATCC) 세포를 CD-CHO 배지(라이프 테크놀로지스(Life Technologies), #10743029)에 0.5x106 세포/㎖로 배양하였다. huB7-H4 또는 cyB7-H4 유전자를 암호화하는 벡터 10 ㎍을 1 ㎖의 Opti-MEM 배지(라이프 테크놀로지스, #31985088) 중의 50 ㎕ LF-LTX(라이프 테크놀로지스, #A12621)와 혼합하였다. 혼합물을 실온에서 20분간 배양하고 CHO 세포의 배양 배지에 가하였다. 세포를 배양을 위해 이산화 탄소 배양기에 넣었다. 24시간 후에, 배양 배지를 새로운 배지로 교체하고 10 ㎍/㎖ 퓨로마이신을 가하였다. 그 후에, 배양 배지를 2 내지 3일마다 새로운 배지로 교체하고, 10-12일의 선택 후에 안정한 CHO-S 세포 풀을 수득하였다.The full-length sequence encoding the human or cynomolgus monkey B7-H4 protein (huB7-H4 or cyB7-H4) was synthesized by Integrated DNA Technology (IDT) (the template sequence of the B7-H4 recombinant protein is shown in all Each was cloned into the modified pcDNA3.1 vector, pcDNA3.1/Puro (Invitrogen #V79020). CHO-S (ATCC) cells were cultured in CD-CHO medium (Life Technologies, #10743029) at 0.5x10 6 cells/ml. 10 μg of vector encoding the huB7-H4 or cyB7-H4 gene was mixed with 50 μl LF-LTX (Life Technologies, #A12621) in 1 ml of Opti-MEM medium (Life Technologies, #31985088). The mixture was incubated at room temperature for 20 minutes and added to the culture medium of CHO cells. Cells were placed in a carbon dioxide incubator for culture. After 24 hours, the culture medium was replaced with fresh medium and 10 μg/ml puromycin was added. Thereafter, the culture medium was replaced with fresh medium every 2-3 days, and a stable pool of CHO-S cells was obtained after 10-12 days of selection.
실시예 2: 마우스 하이브리도마 및 항체 서열의 획득Example 2: Acquisition of mouse hybridomas and antibody sequences
총 5마리의 Balb/c 및 5마리의 A/J 암컷 10-주된 마우스를 인간 항원 huB7-H4-Fc로 면역시켰다. 시그마(Sigma) 완전 프로인트 항원보강제(CFA) 및 시그마 불완전 프로인트 항원보강제(IFA)를 사용하였다. 면역원 및 면역 항원보강제를 충분히 혼합하고 1:1의 비로 유화시켜 안정한 "유중 수적형" 액체를 제조하였다. 주입 용량은 25 ㎍/200 ㎕/마우스였다.A total of 5 Balb/c and 5 A/J female 10-week-old mice were immunized with the human antigen huB7-H4-Fc. Sigma complete Freund's adjuvant (CFA) and Sigma incomplete Freund's adjuvant (IFA) were used. A stable "water-in-oil" liquid was prepared by thoroughly mixing the immunogen and adjuvant and emulsifying in a 1:1 ratio. The injection dose was 25 μg/200 μl/mouse.
01일: 1차 면역화, 완전 프로인트 항원보강제.Day 01: 1st immunization, complete Freund's adjuvant.
21일: 2차 면역화, 불완전 프로인트 항원보강제.Day 21: 2nd immunization, incomplete Freund's adjuvant.
35일: 3차 면역화, 불완전 프로인트 항원보강제.Day 35: 3rd immunization, incomplete Freund's adjuvant.
42일: 혈액 샘플링 및 혈청 역가 시험(3회 면역화 후 혈액).Day 42: Blood sampling and serum titer testing (blood after 3 immunizations).
49일: 4차 면역화, 불완전 프로인트 항원보강제.Day 49: 4th immunization, incomplete Freund's adjuvant.
56일: 혈액 샘플링 및 혈청 역가 시험(4회 면역화 후 혈액).Day 56: Blood sampling and serum titer testing (blood after 4 immunizations).
간접적인 ELISA 방법을 사용하여 항체 또는 혈청의 친화성을 검출하였다: huB7-H4-His 단백질을 PBS pH 7.4로 1 ㎍/㎖의 농도로 희석하고, 100 ㎕/웰로 96-웰 고-친화성 ELISA 플레이트에 가하고, 밤새(16-20시간) 배양을 위해 4℃에서 냉장보관하였다. 플레이트를 PBST(0.05% 트윈(Tween)-20을 함유하는 pH 7.4 PBS)로 4회 세척하였다. PBST로 희석된 3% 소 혈청 알부민(BSA) 차단 용액을 150 ㎕/웰로 가하고 차단을 위해 실온에서 1시간 동안 배양하였다. 차단 완료 후에, 차단 용액을 버리고, 플레이트를 PBST 완충제로 4회 세척하였다. 시험하고자 하는 항체 또는 혈청을 3% BSA를 함유하는 PBST로 희석하여 1 μM로부터 시작하는 10회 용량(10-배 희석)의 구배를 획득하고, 이를 100 ㎕/웰로 미세적정 플레이트에 가하고 실온에서 1시간 동안 배양하였다. 배양의 완료 후에, 플레이트를 PBST로 4회 세척하고, 3% BSA를 함유하는 PBST로 희석된 HRP-표지된 염소 항-인간 2차 항체(애브캠(Abcam), cat#ab97225)를 100 ㎕/웰로 가하고, 실온에서 1시간 동안 배양하였다. 플레이트를 PBST로 4회 세척하고, 이어서 TMB 색원성 기질(셀 시그널링 테크놀로지(Cell Signaling Technology), cat#7004S)을 100 ㎕/웰로 가하고 실온의 암실에서 1분간 배양하였다. 정지액(셀 시그널링 테크놀로지, cat#7002S)을 100 ㎕/웰로 가하여 반응을 종료시켰다. 흡광도 값을 미세플레이트 판독기(바이오텍(BioTek), 시너지(Synergy) H1 모델)로 450 ㎚에서 판독하였다. 데이터를 분석하여 인간 B7-H4 항원에 대한 항체 또는 혈청의 결합 친화성을 획득하였다.Affinity of antibody or serum was detected using an indirect ELISA method: huB7-H4-His protein was diluted with PBS pH 7.4 to a concentration of 1 μg/ml, and 96-well high-affinity ELISA at 100 μl/well. Plates were applied and stored refrigerated at 4°C for overnight (16-20 hours) incubation. Plates were washed 4 times with PBST (pH 7.4 PBS containing 0.05% Tween-20). A 3% bovine serum albumin (BSA) blocking solution diluted with PBST was added at 150 μl/well and incubated for 1 hour at room temperature for blocking. After blocking was complete, the blocking solution was discarded and the plate washed 4 times with PBST buffer. The antibody or serum to be tested is diluted with PBST containing 3% BSA to obtain a gradient of 10 doses (10-fold dilution) starting from 1 μM, which is added to microtiter plates at 100 μl/well and 1 at room temperature. incubated for hours. After completion of the incubation, the plates were washed 4 times with PBST and 100 μΐ// It was added to the wells and incubated for 1 hour at room temperature. Plates were washed 4 times with PBST, then TMB chromogenic substrate (Cell Signaling Technology, cat#7004S) was added at 100 μl/well and incubated for 1 minute in the dark at room temperature. Stop solution (Cell Signaling Technology, cat#7002S) was added at 100 μl/well to terminate the reaction. Absorbance values were read at 450 nm with a microplate reader (BioTek, Synergy H1 model). The data were analyzed to obtain the binding affinity of the antibody or serum to the human B7-H4 antigen.
혈청 역가 및 세포 표면 항원에 결합하는 면역된 마우스 혈청의 능력을 간접 ELISA 방법을 사용하여 평가하였다. 세포 융합을 역가의 검출 결과(100,000배 초과의 희석)에 따라 수행하였다. 높은 혈청 역가, 친화성 및 FACS 결합을 갖는 면역된 마우스를 하나의 최종 면역화를 위해 선택하고 이어서 희생시켰다. 비장 세포 및 SP2/0 골수종 세포를 융합시키고 도말하여 하이브리도마를 수득하였다. 표적 하이브리도마를 간접 ELISA에 의해 선별하고 단클론 세포주를 제한-희석 방법에 의해 확립시켰다. 수득된 양성 항체 균주 중에서, 비-특이적 결합 항체를 발현하는 하이브리도마 균주를, huB7-H4 및 cyB7-H4를 안정하게 발현하는 CHO-S 세포와 블랭크(blank) CHO-S 세포를 비교함으로써 추가로 제외시켰다. 표적 하이브리도마를 실시예 5의 시험관내 세포 결합 실험의 방법과 유사한 방법을 사용하여 선별하고, 제한-희석 방법에 의해 단클론 세포 균주로서 확립시켰다. 대수 성장기의 하이브리도마 세포를 수집하였다. RNA를 트리졸(Trizol)(인비트로젠, 15596-018)로 추출하고, 역 전사를 가하였다(프라임스크립트(PrimeScript)(상표) 역전사효소, 타카라(Takara) #2680A). 역전사에 의해 수득된 dDNA를 마우스 Ig-프라이머 세트(노바겐(Novagen), TB326 Rev.B 0503)와 함께 PCR에 의해 증폭시키고 서열분석하였다. 최종적으로, 쥐 항체의 4개 균주의 서열을 항체-약물 접합체의 인간화 및 구성을 위해 획득하였다.Serum titers and the ability of immunized mouse sera to bind cell surface antigens were assessed using an indirect ELISA method. Cell fusion was performed according to the detection result of titer (>100,000 fold dilution). Immunized mice with high serum titer, affinity and FACS binding were selected for one final immunization and then sacrificed. Splenocytes and SP2/0 myeloma cells were fused and plated to obtain hybridomas. Target hybridomas were selected by indirect ELISA and monoclonal cell lines were established by limit-dilution methods. Among the obtained positive antibody strains, hybridoma strains expressing non-specific binding antibodies were compared with CHO-S cells stably expressing huB7-H4 and cyB7-H4 with blank CHO-S cells. further excluded. Target hybridomas were selected using a method similar to that of the in vitro cell binding experiment of Example 5, and established as a monoclonal cell strain by the limit-dilution method. Hybridoma cells in the logarithmic growth phase were collected. RNA was extracted with Trizol (Invitrogen, 15596-018) and subjected to reverse transcription (PrimeScript® Reverse Transcriptase, Takara #2680A). The dDNA obtained by reverse transcription was amplified by PCR with a mouse Ig-primer set (Novagen, TB326 Rev.B 0503) and sequenced. Finally, the sequences of four strains of murine antibodies were obtained for humanization and construction of antibody-drug conjugates.
쥐 단클론 항체 2G6의 중쇄 및 경쇄 가변 영역 서열은 하기와 같다:The heavy and light chain variable region sequences of the murine monoclonal antibody 2G6 are as follows:
2G6 HCVR2G6 HCVR
EVQLVESGGGLVKPGGSLKLSCAASGFTFSRYGMSWVRQTPEKRLEWVAGINGGGSYTYYLDTVKGRFTISRDNSRNTLYLQMSSLRSEDTAMYYCVSQGSNYYFDYWGQGTTLTVSS 서열번호 46EVQLVESGGGLVKPGGSLKLSCAASGFTFSRYGMSWVRQTPEKRLEWVAGINGGGSYTYYLDTVKGRFTISRDNSRNTLYLQMSSLRSEDTAMYYCVSQGSNYYFDYWGQGTTLTVSS SEQ ID NO:46
2G6 LCVR2G6 LCVR
DIRMTQSPSSMSVSLGDTVSITCHASQGISSNIGWLQQKPGKSFKALIYHGTNLEDGVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPYTFGGGTKLEIK 서열번호 47.DIRMTQSPSSMSVSLGDTVSITCHASQGISSNIGWLQQKPGKSFKALIYHGTNLEDGVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPYTFGGGTKLEIK SEQ ID NO:47.
쥐 단클론 항체 2G6의 중쇄 및 경쇄 가변 영역은 하기의 CDR 서열을 포함한다:The heavy and light chain variable regions of murine monoclonal antibody 2G6 comprise the following CDR sequences:
쥐 단클론 항체 2F7의 중쇄 및 경쇄 가변 영역의 서열은 하기와 같다:The sequences of the heavy and light chain variable regions of the murine monoclonal antibody 2F7 are as follows:
2F7 HCVR2F7 HCVR
EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYYMSWVRQTPEKRLEWVAYVSSGGGSTYYSDSVKGRFTISRDNAKNTLYLQMSSLKPEDTAMYYCTRESYSQGNYFDYWGQGTTLTVSS 서열번호 48EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYYMSWVRQTPEKRLEWVAYVSSGGGSTYYSDSVKGRFTISRDNAKNTLYLQMSSLKPEDTAMYYCTRESYSQGNYFDYWGQGTTLTVSS SEQ ID NO: 48
2F7 LCVR2F7 LCVR
DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKFASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFSLTFGAGTKLELK 서열번호 49.DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKFASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFSLTFGAGTKLELK SEQ ID NO: 49.
쥐 단클론 항체 2F7의 중쇄 및 경쇄 가변 영역은 하기의 CDR 서열을 포함한다:The heavy and light chain variable regions of murine monoclonal antibody 2F7 comprise the following CDR sequences:
쥐 단클론 항체 2F8의 중쇄 및 경쇄 가변 영역의 서열은 하기와 같다:The sequences of the heavy and light chain variable regions of the murine monoclonal antibody 2F8 are as follows:
2F8 HCVR2F8 HCVR
QVQLQQPGSVLVRPGASVKLSCKASGYTFTNSWMNWAKLRPGQGLEWIGGIYPNSGNIEYNEKFKGKATLTVDTSSSTAYMDLTSLTSEDSAVYYCARDSRFSYWGQGTLVTVSA 서열번호 50QVQLQQPGSVLVRPGASVKLSCKASGYTFTNSWMNWAKLRPGQGLEWIGGIYPNSGNIEYNEKFKGKATLTVDTSSSTAYMDLTSLTSEDSAVYYCARDSRFSYWGQGTLVTVSA SEQ ID NO: 50
2F8 LCVR2F8 LCVR
DIVMTQSHKFMSTSVGDRVSITCKASQDVRTAVAWYQQKPGQSPKLLISSTSYRYTGVPDRFTGSGSGTDFTFIISSVQAEDLAVYYCQQHYSTPLTFGAGTKLELK 서열번호 51.DIVMTQSHKFMSTSVGDRVSITCKASQDVRTAVAWYQQKPGQSPKLLISSTSYRYTGVPDRFTGSGSGTDFTFIISSVQAEDLAVYYCQQHYSTPLTFGAGTKLELK SEQ ID NO: 51.
쥐 단클론 항체 2F8의 중쇄 및 경쇄 가변 영역은 하기의 CDR 서열을 포함한다:The heavy and light chain variable regions of murine monoclonal antibody 2F8 comprise the following CDR sequences:
쥐 단클론 항체 1C9의 중쇄 및 경쇄 가변 영역의 서열은 하기와 같다:The sequences of the heavy and light chain variable regions of the murine monoclonal antibody 1C9 are as follows:
1C9 HCVR1C9 HCVR
QVQLQQPGSVLVRPGASVKLSCKASGDTFTTYWMNWVKQRPGQGLEWIGGIYLNSGSSEYNEKFKGKATLSVDTSSSTAYMDLSSLTSEDSAVYYCARDSRFSYWGQGTLVTVSA 서열번호 52QVQLQQPGSVLVRPGASVKLSCKASGDTFTTYWMNWVKQRPGQGLEWIGGIYLNSGSSEYNEKFKGKATLSVDTSSSTAYMDLSSLTSEDSAVYYCARDSRFSYWGQGTLVTVSA SEQ ID NO: 52
1C9 LCVR1C9 LCVR
DIVMTQSHKFLSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPELLISSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYNTPLTFGAGTQLELK 서열번호 53.DIVMTQSHKFLSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPELLISSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYNTPLTFGAGTQLELK SEQ ID NO:53.
쥐 단클론 항체 1C9의 중쇄 및 경쇄 가변 영역은 하기의 CDR 서열을 포함한다:The heavy and light chain variable regions of murine monoclonal antibody 1C9 comprise the following CDR sequences:
실시예 3: 쥐 항체의 인간화 실험Example 3: Humanization experiment of murine antibody
쥐 항-인간 B7-H4 단클론 항체의 인간화를 당해 분야의 다수의 문서에 공개된 바와 같은 방법을 사용하여 수행하였다. 간단히, 모(쥐 항체) 불변 도메인을 인간 불변 도메인으로 교체하였다. 본 발명에서, 인간 생식세포계열 항체 서열을 쥐 항체와 인간 항체간의 상동성에 따라 선택하였고, 쥐 항체 2G6, 2F7, 2F8 및 1C9를 인간화하였다. 쥐 항체 2G6 및 2F7의 CDR 영역을 상기 선택된 상응하는 인간화된 주형상에 접목시켜 상기 인간화된 가변 영역을 교체하고, 이어서 IgG 불변 영역(바람직하게는 중쇄의 경우 IgG1, 및 경쇄의 경우 κ)과 재조합시켰다. 이어서, 쥐 항체의 3차원 구조에 기반하여, 내장된 잔기, CDR 영역과 직접 상호작용하는 잔기 및 VL 및 VH의 형태에 상당한 영향을 미치는 잔기를 역 돌연변이시키고, CDR 영역의 화학적으로 불안정한 아미노산 잔기를 최적화하였고, 여기서 쥐 단클론 항체 2F8의 HCDR1은 GYTFTSSWMN(서열번호 43)에 최적화되었고, HCDR2는 GIYPNRGNIEY NEKFKG(서열번호 44)에 최적화되었고, 쥐 단클론 항체 1C9의 HCDR2는 YLNRGS(서열번호 45)에 최적화되었고, 하기 경쇄 및 중쇄 가변 영역 서열의 조합을 포함하는 설계된 인간화된 항체를 수득하였다.Humanization of the murine anti-human B7-H4 monoclonal antibody was performed using methods as published in numerous documents in the art. Briefly, the parent (murine antibody) constant domain was replaced with a human constant domain. In the present invention, human germline antibody sequences were selected according to the homology between murine and human antibodies, and murine antibodies 2G6, 2F7, 2F8 and 1C9 were humanized. The CDR regions of murine antibodies 2G6 and 2F7 were grafted onto the selected corresponding humanized templates to replace the humanized variable regions, followed by recombination with an IgG constant region (preferably IgGl for heavy chain, and κ for light chain). made it Then, based on the three-dimensional structure of the murine antibody, built-in residues, residues that directly interact with the CDR regions, and residues that significantly affect the conformation of VL and VH were reverse mutated, and chemically unstable amino acid residues of the CDR regions were Optimized, wherein HCDR1 of murine monoclonal antibody 2F8 was optimized for GYTFTSSWMN (SEQ ID NO: 43), HCDR2 was optimized for GIYPNRGNIEY NEKFKG (SEQ ID NO: 44), and HCDR2 of murine monoclonal antibody 1C9 was optimized for YLNRGS (SEQ ID NO: 45) , A designed humanized antibody comprising a combination of the following light and heavy chain variable region sequences was obtained.
인간화된 항체 hu2G6의 중쇄 및 경쇄 가변 영역은 하기와 같다:The heavy and light chain variable regions of the humanized antibody hu2G6 are as follows:
hu2G6 HCVRhu2G6 HCVR
EVQLLESGGGLVQPGGSLRLSCAASGFTFSRYGMSWVRQAPGKGLEWVSGINGGGSYTYYLDTVKGRFTISRDNARNTLYLQMSSLRAEDTAVYYCVSQGSNYYFDYWGQGTLVTVSS 서열번호 15EVQLLESGGGLVQPGGSLRLSCAASGFTFSRYGMSWVRQAPGKGLEWVSGINGGGSYTYYLDTVKGRFTISRDNARNTLYLQMSSLRAEDTAVYYCVSQGSNYYFDYWGQGTLVTVSS SEQ ID NO: 15
hu2G6 LCVRhu2G6 LCVR
DIRMTQSPSSLSASVGDRVTITCHASQGISSNIGWLQQKPGKAPKALIYHGTNLEDGVPSRFSGSGSGADYTLTISSLQPEDFATYYCVQYAQFPYTFGGGTKVEIK 서열번호 16DIRMTQSPSSLSASVGDRVTITCHASQGISSNIGWLQQKPGKAPKALIYHGTNLEDGVPSRFSGSGSGADYTLTISSLQPEDFATYYCVQYAQFPYTFGGGTKVEIK SEQ ID NO: 16
인간화된 항체 hu2F7의 중쇄 및 경쇄 가변 영역은 하기와 같다:The heavy and light chain variable regions of the humanized antibody hu2F7 are as follows:
hu2F7 HCVRhu2F7 HCVR
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYYMSWVRQAPGKGLEWVAYVSSGGGSTYYSDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCTRESYSQGNYFDYWGQGTTVTVSS 서열번호 17EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYYMSWVRQAPGKGLEWVAYVSSGGGSTYYSDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCTRESYSQGNYFDYWGQGTTVTVSS SEQ ID NO: 17
hu2F7 LCVRhu2F7 LCVR
EIVMTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQSPRLLIKFASQSISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQNGHSFSLTFGQGTKLEIK 서열번호 18.EIVMTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQSPRLLIKFASQSISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQNGHSFSLTFGQGTKLEIK SEQ ID NO: 18.
인간화된 항체 hu2F8의 중쇄 및 경쇄 가변 영역은 하기와 같다:The heavy and light chain variable regions of the humanized antibody hu2F8 are as follows:
hu2F8 HCVRhu2F8 HCVR
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSSWMNWVRQAPGQRLEWMGGIYPNRGNIEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSS 서열번호 35EVQLVQSGAEVKKPGASVKVSCKASGYTFTSSWMNWVRQAPGQRLEWMGGIYPNRGNIEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSS SEQ ID NO: 35
hu2F8 LCVRhu2F8 LCVR
DIQMTQSPSSLSASVGDRVTITCKASQDVRTAVAWYQQKPGKAPKLLISSTSYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPLTFGGGTKVEIK 서열번호 36DIQMTQSPSSLSASVGDRVTITCKASQDVRTAVAWYQQKPGKAPKLLISSTSYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPLTFGGGTKVEIK SEQ ID NO: 36
인간화된 항체 hu1C9의 중쇄 및 경쇄 가변 영역은 하기와 같다:The heavy and light chain variable regions of the humanized antibody hu1C9 are as follows:
hu1C9 HCVRhu1C9 HCVR
EVQLVQSGAEVKKPGASVKVSCKASGDTFTTYWMNWVRQAPGQRLEWMGGIYLNRGSSEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSS 서열번호 37EVQLVQSGAEVKKPGASVKVSCKASGDTFTTYWMNWVRQAPGQRLEWMGGIYLNRGSSEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSS SEQ ID NO:37
hu1C9 LCVRhu1C9 LCVR
DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLISSASYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYNTPLTFGGGTKVEIK 서열번호 38.DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLISSASYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYNTPLTFGGGTKVEIK SEQ ID NO: 38.
가변 영역들을 IgG 불변 영역(바람직하게는 중쇄의 경우 IgG1, 및 경쇄의 경우 κ)과 재조합시켰다. 예시적인 중쇄 및 경쇄 불변 영역 서열을 하기와 같이 나타낸다:The variable regions were recombined with an IgG constant region (preferably IgGl for heavy chain, and κ for light chain). Exemplary heavy and light chain constant region sequences are shown below:
IgG1 C:IgG1 C:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 서열번호 54ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 54
Ig 카파 C:Ig Kappa C:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 서열번호 55.RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 55.
하기의 예시적인 경쇄 및 중쇄로 이루어진 인간화된 항체를 하기의 연결 후에 수득하였다:A humanized antibody consisting of the following exemplary light and heavy chains was obtained after ligation:
hu2G6 HChu2G6 HC
EVQLLESGGGLVQPGGSLRLSCAASGFTFSRYGMSWVRQAPGKGLEWVSGINGGGSYTYYLDTVKGRFTISRDNARNTLYLQMSSLRAEDTAVYYCVSQGSNYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKEVQLLESGGGLVQPGGSLRLSCAASGFTFSRYGMSWVRQAPGKGLEWVSGINGGGSYTYYLDTVKGRFTISRDNARNTLYLQMSSLRAEDTAVYYCVSQGSNYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
서열번호 19SEQ ID NO: 19
hu2G6 LChu2G6 LC
DIRMTQSPSSLSASVGDRVTITCHASQGISSNIGWLQQKPGKAPKALIYHGTNLEDGVPSRFSGSGSGADYTLTISSLQPEDFATYYCVQYAQFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDIRMTQSPSSLSASVGDRVTITCHASQGISSNIGWLQQKPGKAPKALIYHGTNLEDGVPSRFSGSGSGADYTLTISSLQPEDFATYYCVQYAQFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVTYVCLLNNFYPREAKVQNSFTLNNFYPREAKVQNSFTLNNFYPREAKVQSSQPEDFATYYCVQYAQFPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVTYVCLLNNFYPREAKVQNSFTLNNFYPREAKVQNSQVKVDNALQSSKHSG
서열번호 20SEQ ID NO: 20
hu2F7 HChu2F7 HC
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYYMSWVRQAPGKGLEWVAYVSSGGGSTYYSDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCTRESYSQGNYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYYMSWVRQAPGKGLEWVAYVSSGGGSTYYSDSVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCTRESYSQGNYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
서열번호 21SEQ ID NO: 21
hu2F7 LChu2F7 LC
EIVMTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQSPRLLIKFASQSISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQNGHSFSLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECEIVMTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQSPRLLIKFASQSISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQNGHSFSLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLSSECTLSYPREAKVQWKVACEKATEKLQSGNSQESNRFYPREAKVQWKVEKVEKLQSGNSQESVNRTEGLQSSKPSTY
서열번호 22SEQ ID NO: 22
hu2F8 HChu2F8 HC
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSSWMNWVRQAPGQRLEWMGGIYPNRGNIEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKEVQLVQSGAEVKKPGASVKVSCKASGYTFTSSWMNWVRQAPGQRLEWMGGIYPNRGNIEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
서열번호 39SEQ ID NO: 39
hu2F8 LChu2F8 LC
DIQMTQSPSSLSASVGDRVTITCKASQDVRTAVAWYQQKPGKAPKLLISSTSYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDIQMTQSPSSLSASVGDRVTITCKASQDVRTAVAWYQQKPGKAPKLLISSTSYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVTKVCLLNNFYPREAKVQQKPGKAPKLLISSTSYRYTGVPSRFSGSGSGTDFTISSLQPEDIATYYCQQHYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVTKVCLLNNFYPREAKVQQKPGKAPKLLISSTSKVQNLNNFYPREAKVQWYESVTHQQDSSGKV
서열번호 40SEQ ID NO: 40
hu1C9HChu1C9HC
EVQLVQSGAEVKKPGASVKVSCKASGDTFTTYWMNWVRQAPGQRLEWMGGIYLNRGSSEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKEVQLVQSGAEVKKPGASVKVSCKASGDTFTTYWMNWVRQAPGQRLEWMGGIYLNRGSSEYNEKFKGRVTLTVDTSASTAYMELSSLRSEDTAVYYCARDSRFSYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
서열번호 41SEQ ID NO: 41
hu1C9 LChu1C9 LC
DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLISSASYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYNTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLISSASYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYNTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVTKVCLLNNFYPREAKVQQKPGKAPKAPKLLISSASYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYNTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVTYVCLLNNFYPREAKVQQKPGKAPKALQSSKNSQNRSVTHQDALQSSKNSQ
서열번호 42SEQ ID NO: 42
실시예 4: 항-B7-H4 인간화된 항체의 발현Example 4: Expression of anti-B7-H4 humanized antibody
재조합 벡터를 인간화된 항체의 서열에 따라 설계하였다. 중쇄 벡터를 하기와 같이 설계하였다: 신호 펩타이드 + 인간화된 중쇄. 경쇄 벡터를 하기와 같이 설계하였다: 신호 펩타이드 + 인간화된 경쇄.Recombinant vectors were designed according to the sequences of humanized antibodies. The heavy chain vector was designed as follows: signal peptide + humanized heavy chain. The light chain vector was designed as follows: signal peptide + humanized light chain.
상기 서열을 pCEP4 벡터(써모피셔(ThermoFisher) #V04450)내에 삽입하였다. 발현 벡터를 상기 설계에 따라 합성하였다. 벡터 플라스미드를 수득하고 대규모로 추출하고 검증을 위한 서열분석을 위해 보냈다. 적격 플라스미드를 PEI(써모피셔 # BMS1003-A)와 함께 인간 293F 세포(써모피셔 # R79007)내에 형질감염시켰다. 293F 세포를 무혈청 배지(상하이 OPM 바이오사이언시즈(Shanghai OPM Biosciences), OPM-293 CD03)와 함께 대수 성장기로 계속해서 배양하고 세포 형질감염에 사용하였다. 21.4 ㎍의 인간화된 항체 경쇄 플라스미드 및 23.6 ㎍의 인가화된 항체 중쇄 플라스미드를 10 ㎖ Opti-MEM(등록상표) I 환원 혈청 배지(GIBCO, 31985-070)에 용해시키고, 잘 혼합하고, 이어서 200 ㎍의 PEI를 가하고 잘 혼합하고, RT에서 15분간 배양하였다. 이어서 50 ㎖의 세포를 가하였다. 세포 배양 조건: 5% CO2, 37℃, 125 rpm/분. 배양 중에, 세포 생육력이 70% 미만일 때까지 1일 및 3일째에 보충물을 가하였다. 세포 상등액을 수집하고, 원심분리하고 여과하였다. 원심분리되고 여과된 세포 배양 배지를 항체 정제 친화성 컬럼상에 로딩하였다. 컬럼을 포스페이트 완충제로 세척하였다. 샘플을 글리신 하이드로클로라이드 완충제(pH 2.7 0.1 M Gly-HCl)로 용출시키고, 1 M 트리스 하이드로클로라이드 pH 9.0으로 중화시키고, 포스페이트 완충제에 대해 투석시켜 최종적으로 정제된 인간화된 항체를 수득하였고, 이를 각 실시예의 실험에 사용할 수 있었다.This sequence was inserted into the pCEP4 vector (ThermoFisher #V04450). Expression vectors were synthesized according to the design above. Vector plasmids were obtained, extracted on a large scale and sent for sequencing for validation. Competent plasmids were transfected into human 293F cells (Thermo Fisher # R79007) with PEI (Thermo Fisher # BMS1003-A). 293F cells were continuously cultured in logarithmic growth phase with serum-free medium (Shanghai OPM Biosciences, OPM-293 CD03) and used for cell transfection. 21.4 μg of humanized antibody light chain plasmid and 23.6 μg of humanized antibody heavy chain plasmid were dissolved in 10 ml Opti-MEM® I reduced serum medium (GIBCO, 31985-070), mixed well, and then 200 μg of PEI was added, mixed well, and incubated for 15 minutes at RT. Then 50 ml of cells were added. Cell culture conditions: 5% CO 2 , 37° C., 125 rpm/min. During culture, supplements were added on
실시예 5: 인간화된 항체의 시험관내 결합 능력의 검출Example 5: Detection of In Vitro Binding Capacity of Humanized Antibodies
설계된 인간화된 항체를 하기와 같이 시험관내 실험으로 시험하였다:The designed humanized antibody was tested in an in vitro experiment as follows:
1. 시험관내 세포 결합 실험:1. In vitro cell binding experiments:
인간 B7-H4를 발현하는 배양된 MX-1 세포(CLS 셀 라인즈 서비스(Cell Lines Service) GmbH #300296)를 수집하고, 세포 밀도를 PBS로 pH 7.4로 조절하고, 세포를 V-모양 바닥을 갖는 96-웰 플레이트상에, 웰당 1x105 세포로 도말하였다. 플레이트를 2000 rpm에서 5분간 원심분리하고 상등액을 제거하였다. 100 ㎕의 구배 희석된 인간화된 항체 용액(0.5% BSA를 함유하는 PBS로 희석, 1 μM로 출발하여, 10회 용량의 3배 구배)을 각 웰에 가하고, 잘 혼합하고 진탕기상에서 4℃에서 1시간 동안 배양하였다. 플레이트를 2000 rpm에서 5분간 원심분리하고 상등액을 제거하였다. 세포를 PBS로 2회 세척하였다. 100 ㎕의 PBS 중 0.5% BSA로 희석된 FITC-표지된 염소 항-인간 2차 항체(애브캠, cat#ab97224)를 각 웰에 가하고, 잘 혼합하고, 진탕기상에서 4℃에서 30분간 배양하였다. 플레이트를 2000 rpm에서 5분간 원심분리하고, 상등액을 제거하였다. 세포를 PBS로 2회 세척하고 이어서 PBS에 재현탁시켰다. 신호를 유식 세포계(벡크만 쿨터(BECKMAN COULTER), 모델 DxFLEX)를 사용하여 검출하고, 농도 곡선을 결과 분석을 위해 플롯팅하였다. 결과는 표 1에 나타낸 바와 같다. 인간화된 항체 hu2G6 및 hu2F7 모두 B7-H4의 고 발현과 함께 MX-1 세포에 양으로 결합한다.Cultured MX-1 cells expressing human B7-H4 (CLS Cell Lines Service GmbH #300296) were harvested, the cell density was adjusted to pH 7.4 with PBS, and the cells were washed with V-shaped bottoms. In 96-well plates with 1x10 5 cells per well. The plate was centrifuged at 2000 rpm for 5 minutes and the supernatant removed. 100 μl of gradient diluted humanized antibody solution (diluted with PBS containing 0.5% BSA, starting at 1 μM, 3-fold gradient of 10 doses) is added to each well, mixed well and at 4° C. on a shaker. Incubated for 1 hour. The plate was centrifuged at 2000 rpm for 5 minutes and the supernatant removed. Cells were washed twice with PBS. FITC-labeled goat anti-human secondary antibody (Abcam, cat#ab97224) diluted in 100 μl of 0.5% BSA in PBS was added to each well, mixed well and incubated for 30 minutes at 4° C. on a shaker. . The plate was centrifuged at 2000 rpm for 5 minutes and the supernatant was removed. Cells were washed twice with PBS and then resuspended in PBS. Signals were detected using a flow cytometer (BECKMAN COULTER, model DxFLEX) and concentration curves were plotted for analysis of the results. The results are as shown in Table 1. Both humanized antibodies hu2G6 and hu2F7 positively bind to MX-1 cells with high expression of B7-H4.
2. 친화성 동역학 실험:2. Affinity Kinetics Experiment:
비아코아(Biacore) 방법은 단백질들간의 친화성 및 동역학을 객관적으로 검출하는데 일반적으로 인정되는 방법이다. 본 발명의 시험하고자 하는 항체의 친화성 및 결합 동역학을 비아코어 T200(GE)에 의해 분석하였다. 본 발명의 시험하고자 하는 항-B7-H4 항체를 비아코어에 의해 제공된 키트 및 NHS 표준 아미노 커플링 방법을 사용하여 CM5(GE) 칩에 공유 결합시켰다. 이어서 동일한 완충제 중에서 희석된 50 nM의 인간 huB7-H4-His 단백질을 10 uL/분의 유량으로 주입하였다. 주입 후에, 샘플을 모두 상기 키트 중의 재생 시약으로 재생시켰다. 항원-항체 결합 동역학을 3분간 추적하고 해리 동역학을 10분간 추적하였다. 획득된 데이터를 GE의 BIAevaluation 소프트웨어를 사용하여 1:1(랭뮤어) 결합 모델로 분석하였다. 상기 방법에 의해 계산된 인간화된 항체의 친화성 동역학 데이터는 표 2에 나타낸 바와 같다. 인간화된 항체 hu2G6, hu2F7, hu2F8 및 hu1C9는 모두 인간 B7-H4 항원 단백질에 대해 강한 친화성을 나타낸다.The Biacore method is a generally accepted method for objectively detecting affinity and kinetics between proteins. The affinity and binding kinetics of the antibodies to be tested of the present invention were analyzed by Biacore T200 (GE). The anti-B7-H4 antibody to be tested of the present invention was covalently linked to a CM5(GE) chip using the kit provided by Biacore and the NHS standard amino coupling method. 50 nM of human huB7-H4-His protein diluted in the same buffer was then injected at a flow rate of 10 uL/min. After injection, all samples were regenerated with the regeneration reagent in the kit. Antigen-antibody binding kinetics were followed for 3 minutes and dissociation kinetics were followed for 10 minutes. The acquired data were analyzed with a 1:1 (Langmuir) binding model using GE's BIAevaluation software. The affinity kinetic data of the humanized antibody calculated by the above method are shown in Table 2. The humanized antibodies hu2G6, hu2F7, hu2F8 and hu1C9 all show strong affinity for the human B7-H4 antigen protein.
ka(1/M*s)bonding speed
k a (1/M*s)
kd (1/s)dissociation rate
k d (1/s)
KD affinity
K D
실시예 6: 항-B7-H4 항체의 세포내이입Example 6: Endocytosis of anti-B7-H4 antibody
본 발명의 항체가 B7-H4에 결합 후에 인간 B7-H4와 함께 세포내이입될 수 있는지의 여부를 시험하기 위해서, MX-1 세포를 평가에 사용하였다. MX-1 세포를 트립신처리하고(먼저 약 2분간 37℃에서 PBS로 1회 세척한다), 수집하고 예비-냉각된 FACS 완충제에 재현탁시켰다. 세포 농도를 1x106 세포/㎖로 조절하였다. 1 ㎖의 세포 현탁액을 EP 튜브에 가하고, 1500 rpm에서 5분간 원심분리하고, 상등액을 제거하였다. 1 ㎖의 상기 제조된 시험하고자 하는 항체를 가하여 세포를 재현탁시켰고, 항체의 최종 농도는 20 ㎍/㎖이었다. 세포를 4℃ 진탕기상에서 1시간 동안 배양하고, 원심분리하고, 상등액을 버렸다(4℃, 1500 rpm x 5분). 세포를 FACS 완충제로 2회 세척하고 상등액을 제거하였다. 100 ㎕의 형광 2차 항체 작업 용액을 각 튜브에 가하여 세포를 재현탁시켰다. 세포를 4℃ 진탕기상에서 30분간 배양하고, 원심분리하고, 상등액을 버렸다(4℃, 1500 rpm x 5분). 세포를 FACS 완충제로 2회 세척하고, 상등액을 제거하였다. 1.0 ㎖의 예온된 MX-1 세포 완전 배지를 각 튜브에 가하여 세포를 재현탁시키고 혼합하였다. 세포 현탁액을 튜브당 200 ㎕로 4개의 튜브에 분액하였다(이들은 각각 0분 군, 블랭크 군, 30분 군 및 2시간 군이었다). 0분 및 블랭크 군은 얼음상에 놓은 반면, 다른 군들은 각각 30분 및 2시간 동안 세포내이입을 위해 37℃ 배양기에 넣었다. 상응하는 시점에서, EP 튜브를 꺼내어 얼음상에 놓아 5분간 예냉시켰다. 모든 처리 군을 원심분리하고 상등액을 버렸다(4℃, 1500 rpm x 5분). 세포를 FACS 완충제로 1회 세척하고 상등액을 제거하였다. 250 ㎕ 스트립 완충제를, 0분 군을 제외한 모든 처리 군의 EP 튜브에 가하고 실온에서 8분간 배양하였다. 세포를 원심분리하고 상등액을 버렸다(4℃, 1500 rpm x 5분). 세포를 FACS 완충제로 2회 세척하고 상등액을 제거하였다. 모든 처리 군에 100 ㎕ 면역염색 정착액을 가하고, 30분 넘게 4℃에 두고, 유식 세포계 DxFlex에 의해 검출하였다. B7-H4 항체의 세포내이입 백분율(%) = (매 시점에서의 평균 형광 강도값 - 블랭크 군의 평균 형광 강도값)/(0 시점에서의 평균 형광 강도값 - 블랭크 군의 평균 형광 강도값) x 100%. 데이터를 표 3에 나타낸다.To test whether the antibody of the present invention can be endocytosed together with human B7-H4 after binding to B7-H4, MX-1 cells were used for evaluation. MX-1 cells were trypsinized (first washed once with PBS at 37° C. for about 2 minutes), collected and resuspended in pre-chilled FACS buffer. The cell concentration was adjusted to 1x10 6 cells/ml. 1 ml of the cell suspension was added to the EP tube, centrifuged at 1500 rpm for 5 minutes, and the supernatant was removed. Cells were resuspended by adding 1 ml of the prepared antibody to be tested, and the final concentration of the antibody was 20 μg/ml. Cells were incubated for 1 h on a 4°C shaker, centrifuged, and the supernatant discarded (4°C, 1500 rpm×5 min). Cells were washed twice with FACS buffer and the supernatant removed. Cells were resuspended by adding 100 μl of fluorescent secondary antibody working solution to each tube. Cells were incubated for 30 min on a 4°C shaker, centrifuged and the supernatant discarded (4°C, 1500 rpm×5 min). Cells were washed twice with FACS buffer and the supernatant removed. 1.0 ml of prewarmed MX-1 cell complete medium was added to each tube to resuspend and mix the cells. The cell suspension was aliquoted into 4 tubes at 200 μl per tube (these were the 0 min group, blank group, 30 min group and 2 h group, respectively). The 0 min and blank groups were placed on ice, while the other groups were placed in a 37° C. incubator for endocytosis for 30 min and 2 h, respectively. At the corresponding time point, the EP tube was removed and placed on ice to pre-cool for 5 minutes. All treatment groups were centrifuged and the supernatant discarded (4° C., 1500 rpm×5 min). Cells were washed once with FACS buffer and the supernatant removed. 250 μl strip buffer was added to the EP tubes of all treatment groups except for the 0 min group and incubated at room temperature for 8 minutes. The cells were centrifuged and the supernatant discarded (4° C., 1500 rpm×5 min). Cells were washed twice with FACS buffer and the supernatant removed. 100 μl immunostaining fixative was added to all treatment groups, placed at 4° C. for over 30 minutes, and detected by flow cytometry DxFlex. B7-H4 antibody endocytosis percentage (%) = (mean fluorescence intensity value at each time point - mean fluorescence intensity value of blank group) / (mean fluorescence intensity value at time point 0 - mean fluorescence intensity value of blank group) x 100%. Data are shown in Table 3.
실시예 7: MC-MMAF에 대한 항체의 접합Example 7: Conjugation of Antibodies to MC-MMAF
본 발명의 항체는 세포 친화성 활성 및 세포내이입 활성을 갖고, 이는 상기 항체를 약물과의 커플링에 적합하게 하여 B7-H4-매개된 질병의 치료를 위한 항체-약물 접합체를 형성시킨다. 커플링 과정을 하기 식에 나타내고, 여기서 Ab는 hu2G6 또는 hu2F7을 나타낸다:The antibodies of the present invention have cell affinity activity and endocytosis activity, which makes the antibody suitable for coupling with drugs to form antibody-drug conjugates for the treatment of B7-H4-mediated diseases. The coupling process is shown in the following formula, wherein Ab represents hu2G6 or hu2F7:
첫 번째 단계에서, S-(3-하이드록시프로필)티오아세테이트(0.7 ㎎, 5.3 mol)를 0.9 ㎖ 아세토나이트릴에 용해시켜, 나중에 사용하기 위한 용액을 형성시켰다. 상기 예비-제조된 S-(3-하이드록시프로필)티오아세테이트의 아세토나이트릴 용액을 pH = 4.3 아세테이트/나트륨 아세테이트 완충제(10.35 ㎎/㎖, 9.0 ㎖, 0.97 mol) 중의 항체에 가하였다. 이어서, 1.0 ㎖의 나트륨 시아노보로하이드라이드(14.1 ㎎, 224 mol)의 수용액을 반응 혼합물에 적가하고 25℃에서 2시간 동안 진탕하에서 반응시켰다. 반응의 완료 후에, 반응 혼합물을 탈염시키고 세파덱스(Sephadex) G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 용액)을 사용하여 정제시켜 생성물 1f의 용액을 수득하였다. 용액을 10 ㎎/㎖로 농축시키고 다음 반응에 바로 사용하였다.In the first step, S-(3-hydroxypropyl)thioacetate (0.7 mg, 5.3 mol) was dissolved in 0.9 ml acetonitrile to form a solution for later use. The above-prepared acetonitrile solution of S-(3-hydroxypropyl)thioacetate was added to the antibody in pH=4.3 acetate/sodium acetate buffer (10.35 mg/ml, 9.0 ml, 0.97 mol). Then, 1.0 ml of an aqueous solution of sodium cyanoborohydride (14.1 mg, 224 mol) was added dropwise to the reaction mixture and reacted at 25° C. for 2 hours under shaking. After completion of the reaction, the reaction mixture was desalted and purified using Sephadex G25 gel column (eluted phase: pH 6.5 0.05 M PBS solution) to obtain a solution of product 1f. The solution was concentrated to 10 mg/ml and used directly in the next reaction.
두 번째 단계에서, 1f 용액(11.0 ㎖)을 0.35 ㎖의 2.0 M 카복시아민 하이드로클로라이드 용액과 함께 가하고 25℃에서 30분간 진탕하에서 반응시켰다. 이어서 반응 용액을 탈염시키고 세파덱스 G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 용액)을 사용하여 정제시켜 생성물 2f(농도 6.17 ㎎/㎖, 14.7 ㎖)의 용액을 수득하였다.In the second step, 1f solution (11.0 ml) was added together with 0.35 ml of 2.0 M carboxyamine hydrochloride solution and reacted at 25° C. for 30 minutes under shaking. Then, the reaction solution was desalted and purified using a Sephadex G25 gel column (eluted phase: pH 6.5 0.05 M PBS solution) to obtain a solution of product 2f (concentration 6.17 mg/ml, 14.7 ml).
세 번째 단계에서, 화합물 MC-MMAF(1.1 ㎎, 1.2 mol, PCT 특허 WO2005081711에 개시된 방법에 의해 제조됨)를 0.3 ㎖ 아세토나이트릴에 용해시키고, 2f 용액(농도 6.17 ㎎/㎖, 3.0 ㎖)에 가하고 25℃에서 4시간 동안 진탕하에서 반응시켰다. 이어서 반응 용액을 탈염시키고 세파덱스 G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 용액)에 의해 정제시키고, 멸균 조건하에서 필터로 여과하여 PBS 완충제 중의 생성물 Ab-MC-MMAF 항체-약물 접합체(3.7 ㎎/㎖, 4.7 ㎖)를 수득하고, 이를 4℃에서 냉장보관하였다. HIC-HPLC에 의해 측정된 생성물 hu2G6-MC-MMAF의 평균값 y는 3.8이었고, hu2G6-MC-MMAF(y=4)의 샘플을 HIC-HPLC 정제에 의해 수득하였다. HIC-HPLC에 의해 측정된 생성물 hu2F7-MC-MMAF의 평균값 y는 3.2였고, hu2F7-MC-MMAF(y=2) 및 hu2F7-MC-MMAF(y=4)의 샘플을 HIC-HPLC 정제에 의해 수득하였다. In the third step, the compound MC-MMAF (1.1 mg, 1.2 mol, prepared by the method disclosed in PCT patent WO2005081711) was dissolved in 0.3 ml acetonitrile and in solution 2f (concentration 6.17 mg/ml, 3.0 ml) and reacted at 25° C. for 4 hours under shaking. The reaction solution was then desalted and purified by Sephadex G25 gel column (eluent phase: pH 6.5 0.05 M PBS solution), filtered under sterile conditions and the product Ab-MC-MMAF antibody-drug conjugate (3.7 mg) in PBS buffer. /mL, 4.7 mL) was obtained, which was refrigerated at 4°C. The average value y of the product hu2G6-MC-MMAF measured by HIC-HPLC was 3.8, and a sample of hu2G6-MC-MMAF (y=4) was obtained by HIC-HPLC purification. The average value y of the product hu2F7-MC-MMAF measured by HIC-HPLC was 3.2, and samples of hu2F7-MC-MMAF (y=2) and hu2F7-MC-MMAF (y=4) were analyzed by HIC-HPLC purification. obtained.
실시예 8: SN-38에 대한 항체의 접합Example 8: Conjugation of Antibody to SN-38
항체-접합된 약물을 하기의 커플링 과정을 통해 제조하였고, 여기서 Ab는 hu2F7을 나타낸다:Antibody-conjugated drugs were prepared via the following coupling procedure, where Ab represents hu2F7:
첫 번째 단계에서, S-(3-하이드록시프로필)티오아세테이트(0.7 ㎎, 5.3 mol)를 0.9 ㎖ 아세토나이트릴에 용해시켜, 나중에 사용하기 위한 용액을 형성시켰다. 상기 예비-제조된 S-(3-하이드록시프로필)티오아세테이트의 아세토나이트릴 용액을 pH = 4.3 아세테이트/나트륨 아세테이트 완충제(10.35 ㎎/㎖, 9.0 ㎖, 0.97 mol) 중의 항체에 가하였다. 이어서, 1.0 ㎖의 나트륨 시아노보로하이드라이드(14.1 ㎎, 224 mol)의 수용액을 반응 혼합물에 적가하고 25℃에서 2시간 동안 진탕하에서 반응시켰다. 반응의 완료 후에, 반응 혼합물을 탈염시키고 세파덱스 G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 용액)을 사용하여 정제시켜 생성물 1h의 용액을 수득하였다. 용액을 10 ㎎/㎖로 농축시키고 다음 반응에 바로 사용하였다.In the first step, S-(3-hydroxypropyl)thioacetate (0.7 mg, 5.3 mol) was dissolved in 0.9 ml acetonitrile to form a solution for later use. The above-prepared acetonitrile solution of S-(3-hydroxypropyl)thioacetate was added to the antibody in pH=4.3 acetate/sodium acetate buffer (10.35 mg/ml, 9.0 ml, 0.97 mol). Then, 1.0 ml of an aqueous solution of sodium cyanoborohydride (14.1 mg, 224 mol) was added dropwise to the reaction mixture and reacted at 25° C. for 2 hours under shaking. After completion of the reaction, the reaction mixture was desalted and purified using a Sephadex G25 gel column (eluent phase: pH 6.5 0.05 M PBS solution) to obtain a solution of product 1h. The solution was concentrated to 10 mg/ml and used directly in the next reaction.
두 번째 단계에서, 1h 용액(11.0 ㎖)을 0.35 ㎖의 2.0 M 카복시아민 하이드로클로라이드 용액과 함께 가하고 25℃에서 30분간 진탕하에서 반응시켰다. 이어서 반응 용액을 탈염시키고 세파덱스 G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 용액)을 사용하여 정제시켜 생성물 2h(농도 6.2 ㎎/㎖, 15.0 ㎖)의 용액을 수득하였다. 상기 2h 용액을 약 10 ㎎/㎖로 농축시키고 다음 반응에 사용하였다.In the second step, 1 h solution (11.0 ml) was added together with 0.35 ml of 2.0 M carboxyamine hydrochloride solution and reacted at 25° C. for 30 minutes under shaking. Then, the reaction solution was desalted and purified using a Sephadex G25 gel column (eluted phase: pH 6.5 0.05 M PBS solution) to obtain a solution of the product 2h (concentration 6.2 mg/ml, 15.0 ml). The 2h solution was concentrated to about 10 mg/ml and used in the next reaction.
세 번째 단계에서, 화합물 MC-VC-PAB-SN-38(1.3 ㎎, 1.2 mol)을 0.3 ㎖ 아세토나이트릴에 용해시키고, 2h 용액(농도 6.2 ㎎/㎖, 3.0 ㎖)에 가하고 25℃에서 4시간 동안 진탕하에서 반응시켰다. 이어서 반응 용액을 탈염시키고 세파덱스 G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 용액)에 의해 정제시키고, 멸균 조건하에서 필터로 여과하여 PBS 완충제 중의 생성물 hu2F7-SN-38 항체-약물 접합체(3.7 ㎎/㎖, 4.7 ㎖)를 수득하고, 이를 4℃에서 냉장보관하였다. 평균값 y를 자외선 방법에 의해 측정하였다. 나트륨 숙시네이트 완충제로 충전된 큐벳을 각각 참조 흡수 셀 및 샘플 측정 흡수 셀에 넣고, 용매 블랭크를 공제한 후에, 시험 용액으로 충전된 큐벳을 샘플 측정 흡수 셀에 넣었다. 280 ㎚ 및 370 ㎚에서의 흡광도를 측정하였다.In the third step, the compound MC-VC-PAB-SN-38 (1.3 mg, 1.2 mol) was dissolved in 0.3 ml acetonitrile, added to a 2h solution (concentration 6.2 mg/ml, 3.0 ml) and 4 at 25°C. The reaction was carried out under shaking for hours. The reaction solution was then desalted and purified by Sephadex G25 gel column (eluent phase: pH 6.5 0.05 M PBS solution), filtered under sterile conditions and the product hu2F7-SN-38 antibody-drug conjugate (3.7 mg) in PBS buffer. /mL, 4.7 mL) was obtained, which was refrigerated at 4°C. The average value y was measured by the ultraviolet method. The cuvette filled with sodium succinate buffer was placed in the reference absorption cell and the sample measurement absorption cell, respectively, and after deducting the solvent blank, the cuvette filled with the test solution was placed in the sample measurement absorption cell. Absorbance at 280 nm and 370 nm was measured.
데이터 처리:Data processing:
항체 함량 Cmab를, 표준 곡선을 확립시키고 280 ㎚ 파장에서의 흡광도를 측정함으로써 측정하였다. 소분자 함량 CDrug을 370 ㎚ 파장에서의 흡광도를 측정함으로써 측정하였다.The antibody content C mab was determined by establishing a standard curve and measuring the absorbance at a wavelength of 280 nm. The small molecule content C Drug was determined by measuring the absorbance at a wavelength of 370 nm.
평균 약물 부하 y = CDrug/Cmab Mean drug load y = C Drug /C mab
생성물 hu2F7-SN-38의 평균값 y = 3.7이 상기 방법에 의해 측정되었다. hu2F7-SN-38(y=4)의 샘플은 UV-HPLC 정제에 의해 수득되었다.The average value y = 3.7 of the product hu2F7-SN-38 was determined by this method. A sample of hu2F7-SN-38 (y=4) was obtained by UV-HPLC purification.
실시예 9: 엑사테칸에 대한 항체의 접합Example 9: Conjugation of Antibodies to Exatecan
1 단계에서, 2a(2 g, 17.2 mmol)를 75 ㎖ 아세토나이트릴에 용해시키고 칼륨 카보네이트(9.27 g, 67.2 mmol), 벤질 브로마이드(20 ㎖, 167.2 mmol) 및 테트라부틸암모늄 요오다이드(620 ㎎, 1.68 mmol)를 연속적으로 가하였다. 반응 용액을 실온에서 48시간 동안 교반하고 규조토를 통해 여과하였다. 필터 케이크를 에틸 아세테이트(20 ㎖)로 세정하였다. 여액을 모으고 감압하에서 농축시켰다. 수득된 잔사를 전개 용매 시스템 C와 함께 실리카 겔 컬럼 크로마토그래피에 의해 정제시켜 생성물 5a(3.2 g, 수율: 90.1%)를 수득하였다.In step 1, 2a (2 g, 17.2 mmol) was dissolved in 75 mL acetonitrile and potassium carbonate (9.27 g, 67.2 mmol), benzyl bromide (20 mL, 167.2 mmol) and tetrabutylammonium iodide (620 mg) , 1.68 mmol) were added successively. The reaction solution was stirred at room temperature for 48 h and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (20 mL). The filtrates were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with a developing solvent system C to give the product 5a (3.2 g, yield: 90.1%).
2 단계에서, 5a(181.3 ㎎, 0.879 mmol) 및 4b(270 ㎎, 0.733 mmol)를 반응 플라스크에 가하고, 6 ㎖ 테트라하이드로퓨란을 가하고 아르곤으로 3회 교체하였다. 반응 혼합물을 빙-수욕에서 0-5℃로 냉각시키고 칼륨 3급-부톡사이드(164 ㎎, 1.46 mmol)를 가하고, 이어서 빙욕을 제거하여 실온으로 가온하고 40분간 교반하였다. 반응 혼합물에 15 ㎖ 빙수를 가하고 에틸 아세테이트(40 ㎖ x 2) 및 클로로포름(20 ㎖ x 5)으로 추출하였다. 유기상을 모으고 농축시켰다. 수득된 잔사를 6 ㎖ 다이옥산에 용해시키고, 3 ㎖ 수, 나트륨 바이카보네이트(73.8 ㎎, 0.879 mmol) 및 9-플루오렌 메틸 클로로포르메이트(190 ㎎, 0.734 mmol)를 가하고 실온에서 2시간 동안 교반하였다. 반응 용액에 30 ㎖ 수를 가하고 에틸 아세테이트(20 ㎖ x 3)로 추출하였다. 유기상을 포화된 염화 나트륨 용액(30 ㎖)으로 세척하고, 무수 황산 나트륨을 사용하여 건조시키고 여과하였다. 여액을 감압하에서 농축시켰다. 수득된 잔사를 전개 용매 시스템 C와 함께 실리카 겔 컬럼 크로마토그래피에 의해 정제시켜 생성물 5b 벤질 10-사이클로프로필-1-(9H-플루오렌-9-일)-3,6-다이옥소-2,9-다이옥사-4,7-다이아자운데크-11-에이트(73 ㎎, 수율: 19.4%)를 수득하였다.In
MS m/z (ESI): 515.0 [M+1].MS m/z (ESI): 515.0 [M+1].
3 단계에서, 5b(30 ㎎, 0.058 mmol)를 6.75 ㎖의 테트라하이드로퓨란 및 에틸 아세테이트(V:V = 2:1)의 혼합된 용매에 용해시키고, 탄소상 팔라듐(18 ㎎, 함량 10%, 건조 기준)을 가하고, 수소로 3회 교체하고, 실온에서 1시간 동안 교반하면서 반응시켰다. 반응 용액을 규조토로 여과하였다. 필터 케이크를 에틸 아세테이트로 세정하였다. 여액을 농축시켜 조 생성물 5c, 10-사이클로프로필-1-(9H-플루오렌-9-일)-3,6-다이옥소-2,9-다이옥사-4,7-다이아자운데크-11-산(20 ㎎)을 수득하고, 이를 정제 없이 다음 반응에 바로 사용하였다.In
MS m/z (ESI): 424.9 [M+1].MS m/z (ESI): 424.9 [M+1].
4 단계에서, 1b(15 ㎎, 28.2 μmol)를 반응 플라스크에 가하고, 1.5 ㎖ N,N-다이메틸포름아미드를 가하고 아르곤으로 3회 교체하였다. 반응 혼합물을 빙수욕에서 0-5℃로 냉각시키고, 1 방울의 트라이에틸아민을 가하고, 조 생성물 5c(20 ㎎, 47.1 μmol)를 가하고, 4-(4,6-다이메톡시-1,3,5-트라이아진-2-일)-4-메틸클로로모르폴린(25.4 ㎎, 86.2 μmol)을 가하고, 빙욕에서 40분간 교반하면서 반응시켰다. 반응 혼합물에 15 ㎖ 수를 가하고, 에틸 아세테이트(20 ㎖ x 3)로 추출하였다. 유기상을 모았다. 유기상을 포화된 염화 나트륨 용액(20 ㎖ x 2)으로 세척하고, 무수 황산 나트륨을 사용하여 건조시키고 여과하였다. 여액을 감압하에서 농축시켰다. 수득된 잔사를 전개 용매 시스템 B와 함께 박층 크로마토그래피에 의해 정제시켜 표제 생성물 5d (9H-플루오렌-9-일)메틸(2-(((1-사이클로프로필-2-(((1S,9S)-9-에틸-5-플루오로-9-하이드록시-4-메틸-10,13-다이옥소-2,3,9,10,13,15-헥사하이드로-1H,12H-벤조[de]피라노[3',4':6,7]인돌로지노[1,2-b]퀴놀린-1-일)아미노)-2-옥소에톡시)메틸)아미노)-2-옥소에틸)카바메이트(23.7 ㎎, 수율: 78.9%)를 수득하였다.In
MS m/z (ESI): 842.1[M+1].MS m/z (ESI): 842.1 [M+1].
5 단계에서, 5d(30 ㎎, 35.7 μmol)를 3 ㎖ 다이클로로메탄에 용해시키고, 1.5 ㎖ 다이에틸아민을 가하고 실온에서 2시간 동안 교반하였다. 반응 용액을 감압하에서 농축시키고, 1.5 ㎖ 톨루엔을 가하고 감압하에서 농축시키고, 2회 반복하였다. 잔사에 4.5 ㎖ n-헥산을 가하고 펄프화하였다. 정치 후에 상등액을 붓고 고체를 유지시켰다. 고체 잔사를 감압하에서 농축시키고 건조 펌핑하여 조 생성물 5e 2-((2-아미노아세트아미도)메톡시)-2-사이클로프로필-N-((1S,9S)-9-에틸-5-플루오로-9-하이드록시-4-메틸-10,13-다이옥소-2,3,9,10,13,15-헥사하이드로-1H,12H-벤조[de]피라노[3',4':6,7]인돌로지노[1,2-b]퀴놀린-1-일)아세트아미드(23 ㎎)를 수득하고, 이를 정제 없이 다음 반응에 바로 사용하였다.In step 5, 5d (30 mg, 35.7 μmol) was dissolved in 3 ml dichloromethane, 1.5 ml diethylamine was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 1.5 ml toluene was added, and concentrated under reduced pressure, which was repeated twice. 4.5 ml n-hexane was added to the residue and it was pulped. After standing, the supernatant was poured and the solid was maintained. The solid residue was concentrated under reduced pressure and pumped to dryness to give crude product 5e 2-((2-aminoacetamido)methoxy)-2-cyclopropyl-N-((1S,9S)-9-ethyl-5-fluoro -9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6 ,7]indologino[1,2-b]quinolin-1-yl)acetamide (23 mg) was obtained, which was used directly in the next reaction without purification.
MS m/z (ESI): 638.0[M+18].MS m/z (ESI): 638.0 [M+18].
6 단계에서, 조 생성물 5e(20 ㎎, 32.3 μmol)를 1 ㎖ N,N-다이메틸포름아미드에 용해시키고 아르곤으로 3회 교체하였다. 반응 혼합물을 빙수욕에서 0-5℃로 냉각시키고, 0.5 ㎖의 4 g(31.8 ㎎, 67.3 μmol)의 N,N-다이메틸포름아미드 용액을 가하고, 4-(4,6-다이메톡시-1,3,5-트라이아진-2-일)-4-메틸클로로모르폴린(27.8 ㎎, 94.3 μmol)을 가하고 빙욕에서 10분간 교반하면서 반응시켰다. 반응 혼합물을 빙욕을 제거하여 실온으로 가온하고 1시간 동안 교반하에서 반응시켜 화합물 5를 생성시켰다. 반응 용액을 고성능 액체 크로마토그래피(분리 조건: 컬럼: XBridge Prep C18 OBD 5 ㎛ 19*250 ㎜; 이동상: A-수(10 mmol NH4OAc): B-아세토나이트릴, 구배 용출, 유량: 18 ㎖/분)에 의해 정제시켰다. 상응하는 성분을 수집하고 감압하에서 농축시켜 생성물 5-A 및 5-B(3.6 ㎎, 2.6 ㎎)를 수득하였다.In step 6, the crude product 5e (20 mg, 32.3 μmol) was dissolved in 1 ml N,N-dimethylformamide and replaced with argon three times. The reaction mixture was cooled to 0-5° C. in an ice-water bath, 0.5 ml of 4 g (31.8 mg, 67.3 μmol) of N,N-dimethylformamide solution was added, and 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methylchloromorpholine (27.8 mg, 94.3 μmol) was added and reacted with stirring in an ice bath for 10 minutes. The reaction mixture was warmed to room temperature by removing the ice bath and reacted under stirring for 1 hour to give compound 5. The reaction solution was subjected to high performance liquid chromatography (separation conditions: column: XBridge Prep C18 OBD 5 μm 19*250 mm; mobile phase: A-water (10 mmol NH 4 OAc): B-acetonitrile, gradient elution, flow rate: 18 mL /min). The corresponding components were collected and concentrated under reduced pressure to give products 5-A and 5-B (3.6 mg, 2.6 mg).
MS m/z (ESI): 1074.4 [M+1].MS m/z (ESI): 1074.4 [M+1].
단일 배열 화합물 5-A(보다 짧은 체류 시간)Single configuration compound 5-A (shorter retention time)
UPLC 분석: 체류 시간 1.14분, 순도: 85%(컬럼: ACQUITY UPLC BEHC18 1.7 ㎛ 2.1*50 ㎜; 이동상: A-수(5 mmol NH4OAc), B-아세토나이트릴).UPLC analysis: retention time 1.14 min, purity: 85% (column: ACQUITY UPLC BEHC18 1.7 μm 2.1*50 mm; mobile phase: A-water (5 mmol NH 4 OAc), B-acetonitrile).
1H NMR (400 MHz, DMSO-d 6): δ 8.60 (t, 1H), 8.51-8.49 (d, 1H), 8.32-8.24 (m, 1H), 8.13-8.02 (m, 2H), 8.02-7.96 (m, 1H), 7.82-7.75 (m, 1H), 7.31 (s, 1H), 7.26-7.15 (m, 4H), 6.99 (s, 1H), 6.55-6.48 (m, 1H), 5.65-5.54 (m, 1H), 5.41 (s, 2H), 5.35-5.15 (m, 3H), 4.74-4.62 (m, 2H), 4.54-4.40 (m, 2H), 3.76-3.64 (m, 4H), 3.62-3.48 (m, 2H), 3.20-3.07 (m, 2H), 3.04-2.94 (m, 2H), 2.80-2.62 (m, 2H), 2.45-2.30 (m, 3H), 2.25-2.15 (m, 2H), 2.15-2.04 (m, 2H), 1.93-1.78 (m, 2H), 1.52-1.39 (m, 3H), 1.34-1.12 (m, 5H), 0.87 (t, 3H), 0.64-0.38 (m, 4H). 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.60 (t, 1H), 8.51-8.49 (d, 1H), 8.32-8.24 (m, 1H), 8.13-8.02 (m, 2H), 8.02 7.96 (m, 1H), 7.82-7.75 (m, 1H), 7.31 (s, 1H), 7.26-7.15 (m, 4H), 6.99 (s, 1H), 6.55-6.48 (m, 1H), 5.65 5.54 (m, 1H), 5.41 (s, 2H), 5.35-5.15 (m, 3H), 4.74-4.62 (m, 2H), 4.54-4.40 (m, 2H), 3.76-3.64 (m, 4H), 3.62-3.48 (m, 2H), 3.20-3.07 (m, 2H), 3.04-2.94 (m, 2H), 2.80-2.62 (m, 2H), 2.45-2.30 (m, 3H), 2.25-2.15 (m) , 2H), 2.15-2.04 (m, 2H), 1.93-1.78 (m, 2H), 1.52-1.39 (m, 3H), 1.34-1.12 (m, 5H), 0.87 (t, 3H), 0.64-0.38 (m, 4H).
단일 배열 화합물 5-B(보다 긴 체류 시간):Single configuration compound 5-B (longer retention time):
UPLC 분석: 체류 시간 1.16분, 순도: 89%(컬럼: ACQUITY UPLC BEHC18 1.7 ㎛ 2.1*50 ㎜; 이동상: A-수(5 mmol NH4OAc), B-아세토나이트릴).UPLC analysis: retention time 1.16 min, purity: 89% (column: ACQUITY UPLC BEHC18 1.7 μm 2.1*50 mm; mobile phase: A-water (5 mmol NH 4 OAc), B-acetonitrile).
1H NMR (400 MHz, DMSO-d 6): δ 8.68-8.60 (m, 1H), 8.58-8.50 (m, 1H), 8.32-8.24 (m, 1H), 8.13-8.02 (m, 2H), 8.02-7.94 (m, 1H), 7.82-7.75 (m, 1H), 7.31 (s, 1H), 7.26-7.13 (m, 4H), 6.99 (s, 1H), 6.55-6.48 (m, 1H), 5.60-5.50 (m, 1H), 5.41 (s, 2H), 5.35-5.15 (m, 3H), 4.78-4.68 (m, 1H), 4.60-4.40 (m, 2H), 3.76-3.58 (m, 4H), 3.58-3.48 (m, 1H), 3.20-3.10 (m, 2H), 3.08-2.97 (m, 2H), 2.80-2.72 (m, 2H), 2.45-2.30 (m, 3H), 2.25-2.13 (m, 2H), 2.13-2.04 (m, 2H), 2.03-1.94 (m, 2H), 1.91-1.78 (m, 2H), 1.52-1.39 (m, 3H), 1.34-1.12 (m, 5H), 0.91-0.79 (m, 3H), 0.53-0.34 (m, 4H). 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.68-8.60 (m, 1H), 8.58-8.50 (m, 1H), 8.32-8.24 (m, 1H), 8.13-8.02 (m, 2H), 8.02-7.94 (m, 1H), 7.82-7.75 (m, 1H), 7.31 (s, 1H), 7.26-7.13 (m, 4H), 6.99 (s, 1H), 6.55-6.48 (m, 1H), 5.60-5.50 (m, 1H), 5.41 (s, 2H), 5.35-5.15 (m, 3H), 4.78-4.68 (m, 1H), 4.60-4.40 (m, 2H), 3.76-3.58 (m, 4H) ), 3.58-3.48 (m, 1H), 3.20-3.10 (m, 2H), 3.08-2.97 (m, 2H), 2.80-2.72 (m, 2H), 2.45-2.30 (m, 3H), 2.25-2.13 (m, 2H), 2.13-2.04 (m, 2H), 2.03-1.94 (m, 2H), 1.91-1.78 (m, 2H), 1.52-1.39 (m, 3H), 1.34-1.12 (m, 5H) , 0.91-0.79 (m, 3H), 0.53-0.34 (m, 4H).
다른 중간체의 제조 방법은 중간체 5의 방법을 참조하였다.For the preparation of other intermediates, refer to the method of intermediate 5.
항체 hu2F7의 PBS 완충된 수용액(pH = 6.5 0.05 M PBS 완충된 수용액; 7.3 ㎖, 13.8 ㎎/㎖, 0.681 μmol)에 37℃에서 트리스(2-카복시에틸) 포스핀(10 mM, 0.347 ㎖, 3.47 μmol)의 제조된 수용액을 가하였다. 반응 혼합물을 수욕 진탕기에 넣고 37℃에서 진탕하에 3시간 동안 반응시켰다. 반응을 종료시키고, 반응 용액을 수욕에서 25℃로 냉각시키고, 14.0 ㎖로 희석하고, 상기 용액 3.3 ㎖을 다음 반응을 위해 취하였다.Tris(2-carboxyethyl)phosphine (10 mM, 0.347 ml, 3.47) in PBS buffered aqueous solution of antibody hu2F7 (pH = 6.5 0.05 M PBS buffered aqueous solution; 7.3 ml, 13.8 mg/ml, 0.681 μmol) at 37°C μmol) of the prepared aqueous solution was added. The reaction mixture was placed in a water bath shaker and reacted at 37° C. under shaking for 3 hours. After the reaction was terminated, the reaction solution was cooled to 25° C. in a water bath, diluted to 14.0 ml, and 3.3 ml of the solution was taken for the next reaction.
화합물 5-A(3.0 ㎎, 3.72 μmol)를 0.15 ㎖ DMSO에 용해시키고 상기 3.3 ㎖ 용액에 가하였다. 반응 혼합물을 수욕 진탕기에 넣고 25℃에서 3시간 동안 진탕하에서 교반하였다. 반응을 종료시켰다. 반응 용액을 탈염하고 세파덱스 G25 젤 컬럼(용출상: pH 6.5 0.05 M PBS 완충된 수용액, 0.001 M EDTA 함유)을 사용하여 정제시켜 PBS 완충제(1.35 ㎎/㎖, 13 ㎖) 중의 Ab-엑사테칸, hu2F7-엑사테칸(화합물 34)의 예시적인 생성물을 수득하고, 이를 4℃에서 보관하였다. 평균값 y를 자외선 방법에 의해 측정하였다. 나트륨 숙시네이트 완충제로 충전된 큐벳을 각각 참조 흡수 셀 및 샘플 측정 흡수 셀에 넣고, 용매 블랭크를 공제한 후에, 시험 용액으로 충전된 큐벳을 샘플 측정 흡수 셀에 넣었다. 280 ㎚ 및 370 ㎚에서의 흡광도를 측정하였다.Compound 5-A (3.0 mg, 3.72 μmol) was dissolved in 0.15 mL DMSO and added to the 3.3 mL solution. The reaction mixture was placed on a water bath shaker and stirred at 25° C. for 3 hours under shaking. The reaction was terminated. The reaction solution was desalted and purified using a Sephadex G25 gel column (eluent phase: pH 6.5 0.05 M PBS buffered aqueous solution, containing 0.001 M EDTA) to Ab-exatecan in PBS buffer (1.35 mg/ml, 13 ml). , obtained an exemplary product of hu2F7-exatecan (Compound 34), which was stored at 4°C. The average value y was measured by the ultraviolet method. The cuvette filled with sodium succinate buffer was placed in the reference absorption cell and the sample measurement absorption cell, respectively, and after deducting the solvent blank, the cuvette filled with the test solution was placed in the sample measurement absorption cell. Absorbance at 280 nm and 370 nm was measured.
데이터 처리:Data processing:
항체 함량 Cmab를, 표준 곡선을 확립시키고 280 ㎚ 파장에서의 흡광도를 측정함으로써 측정하였다. 소분자 함량 CDrug을 370 ㎚ 파장에서의 흡광도를 측정함으로써 측정하였다.The antibody content C mab was determined by establishing a standard curve and measuring the absorbance at a wavelength of 280 nm. The small molecule content C Drug was determined by measuring the absorbance at a wavelength of 370 nm.
평균 약물 부하 y = CDrug/Cmab Mean drug load y = C Drug /C mab
예시적인 생성물 hu2F7-엑사테칸(화합물 34)에 관하여, y가 상기 방법에 의해 7.6인 것으로 측정되었다. hu2F7-엑사테칸(y=8)의 샘플은 UV-HPLC 정제에 의해 수득되었다.For the exemplary product hu2F7-exatecan (Compound 34), y was determined to be 7.6 by this method. A sample of hu2F7-exatecan (y=8) was obtained by UV-HPLC purification.
다른 항체 접합체의 제조 방법은 화합물 34의 방법을 참조하였다.For the preparation of other antibody conjugates, refer to the method of compound 34.
실시예 10: 종양 세포에 대한 항체-약물 접합체의 사멸 활성Example 10: Killing activity of antibody-drug conjugates against tumor cells
종양 세포에 대한 본 발명의 항체-약물 접합체의 사멸 효과를 시험하기 위해서, MX-1 유방암 세포를 평가에 사용하였다. MX-1 세포를 수집하고, 원심분리하고 카운트하였다. 세포 밀도를 완전 배지로 0.44x106 세포/㎖로 조절하고, 세포를 백색 96-웰 플레이트의 60 웰에, 웰당 90 ㎕로 40,000의 세포수로 도말하였다. 나머지 말초 웰에 100 ㎕ PBS를 가하였다. 세포 플레이트를 37℃, 5% CO2 배양기에 넣고 밤새 배양하였다. 실험 2일째에, 항체-약물 접합체 용액을, 1000 nM의 농도로 출발하여(3배 희석 및 9개 농도), 96-웰 V-바닥 플레이트에서 PBS로 제조하였다. 제조의 완료 후에, 용액을 백색 96-웰 플레이트에 웰당 10 ㎕로 중복해서 가하였다. 세포 플레이트를 37℃, 5% CO2 배양기에 넣고 배양을 72시간 동안 지속시켰다. 실험 5일째에, 플레이트를 검출하고 판독하였다. 세포 배양 플레이트를 꺼냈다. 2개의 대조용 웰을 설정하였다. 40,000 세포를 함유하는 100 ㎕ 배지를 각 웰에 가하고, 실온으로 평형화 후에, 50 ㎕ CTG 용액(프로메가 G7573)을 각 웰에 가하였다. 혼합물을 진탕하고 혼합하고, 암실에 두고 10분간 방치하고, 이어서 미세플레이트 판독기의 발광 프로그램을 사용하여 검출하였다. 최대 사멸율 = (1-1000 nM 웰의 형광값/대조용 웰의 형광값)%. 실험 결과는 표 4에 나타낸 바와 같다:To test the killing effect of the antibody-drug conjugate of the present invention on tumor cells, MX-1 breast cancer cells were used for evaluation. MX-1 cells were harvested, centrifuged and counted. Cell density was adjusted to 0.44× 10 6 cells/ml with complete medium, and cells were plated in 60 wells of white 96-well plates at 90 μl per well at a cell count of 40,000. 100 μl PBS was added to the remaining peripheral wells. The cell plate was placed in an incubator at 37° C., 5% CO 2 and incubated overnight. On
실시예 11: 종양 세포의 성장에 대한 항체-약물 접합체의 억제 효과Example 11: Inhibitory effect of antibody-drug conjugates on the growth of tumor cells
종양 세포에 대한 본 발명의 항체-약물 접합체의 사멸 효과를 시험하기 위해서, SK-BR-3(ATCC #HTB30) 유방암 세포를 평가에 사용하였다. SK-BR-3 세포를 수집하고, 원심분리하고 카운트하였다. 세포 밀도를 완전 배지로 0.44x106 세포/㎖로 조절하고, 세포를 백색 96-웰 플레이트의 60 웰에, 웰당 90 ㎕로 40,000의 세포수로 도말하였다. 나머지 말초 웰에 100 ㎕ PBS를 가하였다. 세포 플레이트를 37℃, 5% CO2 배양기에 넣고 밤새 배양하였다. 실험 2일째에, 항체-약물 접합체 용액을, 1000 nM의 농도로 출발하여(3배 희석 및 9개 농도), 96-웰 V-바닥 플레이트에서 PBS로 제조하였다. 제조의 완료 후에, 용액을 백색 96-웰 플레이트에 웰당 10 ㎕로 중복해서 가하였다. 2개의 다른 대조용 웰을 설정하고 10 ㎕ PBS를 각 웰에 가하였다. 세포 플레이트를 37℃, 5% CO2 배양기에 넣고 배양을 72시간 동안 지속시켰다. 실험 5일째에, 플레이트를 검출하고 판독하였다. 세포 배양 플레이트를 꺼냈다. 실온으로 평형화 후에, 50 ㎕ CTG 용액(프로메가 G7573)을 각 웰에 가하였다. 혼합물을 진탕하고 혼합하고, 암실에 두고 10분간 방치하고, 이어서 미세플레이트 판독기의 발광 프로그램을 사용하여 검출하였다. 최대 억제율 = (1-1000 nM 웰의 형광값/대조용 웰의 형광값)%. 실험 결과는 표 5에 나타낸 바와 같다:In order to test the killing effect of the antibody-drug conjugate of the present invention on tumor cells, SK-BR-3 (ATCC #HTB30) breast cancer cells were used for evaluation. SK-BR-3 cells were harvested, centrifuged and counted. Cell density was adjusted to 0.44× 10 6 cells/ml with complete medium, and cells were plated in 60 wells of white 96-well plates at 90 μl per well at a cell count of 40,000. 100 μl PBS was added to the remaining peripheral wells. The cell plate was placed in an incubator at 37° C., 5% CO 2 and incubated overnight. On
실시예 12: MMAF에 접합된 항체-약물 접합체의 생체내 효능의 평가Example 12: Evaluation of In Vivo Efficacy of Antibody-Drug Conjugates Conjugated to MMAF
마우스에서 MX-1 세포로 이식된 종양을 형성시킨 후에, 본 발명의 항체-약물 접합체의 항-종양 효과를 평가하였다. 5x106 MX-1 세포를 면역결핍 누드 마우스(BALB/c Nude)에 피하 주입하였다. 2주 후에, 항체-약물 접합체 hu2G6-MC-MMAF 및 hu2F7-MC-MMAF의 정맥내 주입을, 주당 1회의 빈도 및 1.5 ㎎/㎏ 또는 3 ㎎/㎏의 용량으로 수행하였다. 인간 IgG1 단백질을 3 ㎎/㎏의 용량으로 대조용으로서 사용하였다. 대조군 또는 투여 군의 각 군에 5마리의 마우스가 존재하였다. 종양 억제율을 종양 부피를 측정하여 계산하였다. 종양 억제율 = 100% - (21일째에 투여 군의 종양 부피 - 0일째에 투여 군의 종양 부피)/(21일째에 대조군의 종양 부피 - 0일째에 대조군의 종양 부피). 실험 결과는 도 1 및 표 6에 나타낸 바와 같다. hu2G6-MC-MMAF 및 hu2F7-MC-MMAF 모두 용량-의존적인 항-종양 효과를 나타낸다. hu2G6-MC-MMAF 및 hu2F7-MC-MMAF 모두 3 ㎎/㎏의 용량에서 100%를 초과하는 종양 억제율을 나타내고, 이는 본 발명의 항체-약물 접합체가 종양 성장을 억제할 뿐만 아니라, 이미 형성된 종양에 대해 사멸 효과를 발휘할 수 있음을 의미한다.After forming tumors transplanted with MX-1 cells in mice, the anti-tumor effect of the antibody-drug conjugate of the present invention was evaluated. 5x10 6 MX-1 cells were subcutaneously injected into immunodeficient nude mice (BALB/c Nude). After 2 weeks, intravenous infusions of the antibody-drug conjugates hu2G6-MC-MMAF and hu2F7-MC-MMAF were performed at a frequency of once per week and at a dose of 1.5 mg/kg or 3 mg/kg. Human IgG1 protein was used as a control at a dose of 3 mg/kg. There were 5 mice in each group of the control or administration group. Tumor inhibition was calculated by measuring tumor volume. Tumor inhibition = 100% - (tumor volume in dosing group on day 21 - tumor volume in dosing group on day 0)/(tumor volume in control group on day 21 - tumor volume in control group on day 0). Experimental results are as shown in FIG. 1 and Table 6. Both hu2G6-MC-MMAF and hu2F7-MC-MMAF show dose-dependent anti-tumor effects. Both hu2G6-MC-MMAF and hu2F7-MC-MMAF showed a tumor inhibition rate of more than 100% at a dose of 3 mg/kg, indicating that the antibody-drug conjugate of the present invention not only inhibits tumor growth, but also inhibits tumor growth in already formed tumors. This means that it can exert a killing effect on
실시예 13: 상이한 약물 부하를 갖는 항체-약물 접합체의 생체내 효능의 평가Example 13: Evaluation of In Vivo Efficacy of Antibody-Drug Conjugates with Different Drug Loads
상이한 약물 부하를 갖는 항체-약물 접합체를 추가로 연구하기 위해서, 항체-약물 접합체를 실시예 7의 방법에 의해 제조하고 HPLC에 의해 정제시켜 hu2F7-MC-MMAF(y=2) 및 hu2F7-MC-MMAF(y=4)를 수득하였다(도 2). 마우스에서 MX-1로 이식된 종양을 형성시킨 후에, 본 발명의 항체-약물 접합체의 항-종양 효과를 평가하였다. 5x106 MX-1 세포를 면역결핍 누드 마우스에 피하 주입하였다. 2주 후에, 항체-약물 접합체 hu2F7-MC-MMAF(y=2) 및 hu2F7-MC-MMAF(y=4)의 정맥내 주입을, 주당 1회의 빈도 및 3 ㎎/㎏의 용량으로 수행하였다. 인간 IgG1 단백질을 3 ㎎/㎏의 용량으로 대조용으로서 사용하였다. 대조군 또는 투여 군의 각 군에 5마리의 마우스가 존재하였다. 종양 억제율을 종양 부피를 측정하여 계산하였다. 종양 억제율 = 100% - (21일째에 투여 군의 종양 부피 - 0일째에 투여 군의 종양 부피)/(21일째에 대조군의 종양 부피 - 0일째에 대조군의 종양 부피). 실험 결과는 도 3 및 표 7에 나타낸 바와 같다. hu2F7-MC-MMAF(y=2) 및 hu2F7-MC-MMAF(y=4) 모두 항-종양 효과를 나타낸다. hu2F7-MC-MMAF(y=4)는 3 ㎎/㎏의 용량에서 hu2F7-MC-MMAF(y=2)보다 더 강한 항-종양 효과를 갖고, 이는 100%를 초과하는 종양 억제율을 나타내고, 이는 hu2F7-MC-MMAF(y=4)가 종양 성장을 억제할 뿐만 아니라, 이미 형성된 종양에 대해 사멸 효과를 발휘할 수 있음을 의미한다(도 4).To further study antibody-drug conjugates with different drug loadings, antibody-drug conjugates were prepared by the method of Example 7 and purified by HPLC to hu2F7-MC-MMAF (y=2) and hu2F7-MC- MMAF (y=4) was obtained ( FIG. 2 ). After forming tumors transplanted with MX-1 in mice, the anti-tumor effects of the antibody-drug conjugates of the present invention were evaluated. 5x10 6 MX-1 cells were subcutaneously injected into immunodeficient nude mice. After 2 weeks, intravenous infusions of the antibody-drug conjugates hu2F7-MC-MMAF (y=2) and hu2F7-MC-MMAF (y=4) were performed at a frequency of once per week and a dose of 3 mg/kg. Human IgG1 protein was used as a control at a dose of 3 mg/kg. There were 5 mice in each group of the control or administration group. Tumor inhibition was calculated by measuring tumor volume. Tumor inhibition = 100% - (tumor volume in dosing group on day 21 - tumor volume in dosing group on day 0)/(tumor volume in control group on day 21 - tumor volume in control group on day 0). Experimental results are as shown in FIG. 3 and Table 7. Both hu2F7-MC-MMAF (y=2) and hu2F7-MC-MMAF (y=4) show anti-tumor effects. hu2F7-MC-MMAF (y=4) had a stronger anti-tumor effect than hu2F7-MC-MMAF (y=2) at a dose of 3 mg/kg, showing a tumor suppression rate of greater than 100%, which This means that hu2F7-MC-MMAF (y=4) can not only inhibit tumor growth, but also exert an apoptotic effect on already formed tumors (Fig. 4).
실시예 14: 엑사테칸에 접합된 항체-약물 접합체의 생체내 효능의 평가Example 14: Evaluation of In Vivo Efficacy of Antibody-Drug Conjugates Conjugated to Exatecan
엑사테칸에 접합된 항체-약물 접합체를 연구하기 위해서, 항체-약물 접합체를 실시예 9의 방법에 의해 제조하고 HPLC에 의해 정제시켜 hu2F7-엑사테칸(화합물 34, y=8)을 수득하였다. 마우스에서 MX-1 세포로 이식된 종양을 형성시킨 후에, 본 발명의 항체-약물 접합체의 항-종양 효과를 평가하였다. 5x106 MX-1 세포를 면역결핍 누드 마우스에 피하 주입하였다. 2주 후에, 항체-약물 접합체 hu2F7-엑사테칸(y=8)의 정맥내 주입을, 주당 1회의 빈도 및 5 ㎎/㎏ 또는 10 ㎎/㎏의 용량으로 수행하였다. 인간 IgG1 단백질을 5 ㎎/㎏의 용량으로 대조용으로서 사용하였다. 대조군 또는 투여 군의 각 군에 5마리의 마우스가 존재하였다. 종양 억제율을 종양 부피를 측정하여 계산하였다. 종양 억제율 = 100% - (18일째에 투여 군의 종양 부피 - 0일째에 투여 군의 종양 부피)/(18일째에 대조군의 종양 부피 - 0일째에 대조군의 종양 부피). 실험 결과는 표 8에 나타낸 바와 같다. hu2F7-엑사테칸은 5 ㎎/㎏ 및 10 ㎎/㎏ 모두의 용량에서 100%를 초과하는 종양 억제율을 나타내고, 이는 hu2F7-엑사테칸(y=8)이 종양 성장을 억제할 뿐만 아니라, 이미 형성된 종양에 대해 사멸 효과를 발휘할 수 있음을 의미한다.To study the antibody-drug conjugate conjugated to exatecan, the antibody-drug conjugate was prepared by the method of Example 9 and purified by HPLC to obtain hu2F7-exatecan (compound 34, y=8). . After forming tumors transplanted with MX-1 cells in mice, the anti-tumor effect of the antibody-drug conjugate of the present invention was evaluated. 5x10 6 MX-1 cells were subcutaneously injected into immunodeficient nude mice. After 2 weeks, intravenous infusion of the antibody-drug conjugate hu2F7-exatecan (y=8) was performed at a frequency of once per week and at a dose of 5 mg/kg or 10 mg/kg. Human IgG1 protein was used as a control at a dose of 5 mg/kg. There were 5 mice in each group of the control or administration group. Tumor inhibition was calculated by measuring tumor volume. Tumor inhibition = 100% - (tumor volume in dosing group on day 18 - tumor volume in dosing group on day 0)/(tumor volume in control group on day 18 - tumor volume in control group on day 0). The experimental results are as shown in Table 8. hu2F7-exatecan exhibits >100% tumor inhibition at both doses of 5 mg/kg and 10 mg/kg, indicating that hu2F7-exatecan (y=8) not only inhibits tumor growth, but also It means that it can exert a killing effect on the formed tumor.
실시예 15: 엑사테칸에 접합된 항체-약물 접합체의 방관자 사멸 활성의 실험Example 15: Exatecan-conjugated antibody-drug conjugate experiment on bystander killing activity
방관자 효과를 통한 B7-H4 음성 세포 사멸에 대한 본 발명의 엑사테칸에 접합된 항체-약물 접합체의 효과를 연구하기 위해서, 음성 B7-H4 발현을 갖는 골수종 세포주에 대한 상기 항체-약물 접합체의 사멸 활성을 ONE-Glo(상표) 루시페라제 분석 검출 키트를 사용하여 검출하였다. MX-1 세포를 검출하고, 원심분리하고, 카운트하고, 완전 배지로 7.5x106 세포/㎖의 세포 현탁액으로 조절하고, 백색 96-웰 플레이트상에 도말하였다. 33 ㎕의 MX-1 세포 현탁액을 "혼합 세포 군"의 각 웰에 가하고, 33 ㎕ PBS를 "단세포 군"의 각 웰에 가하였다. 음성 B7-H4 발현을 갖는 NCI-H929-LUC 종양 세포(코바이오어(Cobioer) 카탈로그 번호 CBP30061L)를 수집하였다. 세포 밀도를 1.5x106 세포/㎖로 조절하였다. 33 ㎕의 NCI-H929-LUC 세포 현탁액을 "혼합 세포 군" 및 "단세포 군"의 각 웰에 가하였다. 세포 플레이트를 37℃, 5% CO2 배양기에 넣고 밤새 배양하였다. 실험 2일째에, 시험하고자 하는 항체-약물 접합체 hu2F7-엑사테칸(화합물 34, y=8)의 최고 농도를 3000 nM로 균일하게 조절하고, 희석하여 9개 용량의 5배 구배를 획득하였다. 33.3 ㎕의 희석된 항체-약물 접합체 작업 용액을 실험 플레이트의 각 웰에 가하고 서서히 혼합하였다. 세포 플레이트를 37℃, 5% CO2 배양기에 넣고 48시간 동안 배양하였다. 세포 배양 플레이트를 꺼내고 실온으로 평형화하였다. 이어서 100 ㎕의 ONE-Glo(상표) 루시페라제 시약(프로메가 E6120)을 각 웰에 가하였다. 세포를 실온의 암실에서 10분간 진탕 및 용해시켰다. 세포 용해물을 1000 rpm/분에서 1분간 원심분리하고, 이어서 웰당 180 ㎕로 투명 바닥을 갖는 96-웰 플레이트로 옮겼다. 플레이트를 미세플레이트 판독기상에서 490 ㎚의 파장에서 판독하였다. 데이터를 그래프패드 프리즘(Graphpad Prism) 소프트웨어를 사용하여 분석하였고, 실험 결과는 표 9에 나타낸 바와 같다. ONE-Glo(상표) 루시페라제 시약은 NCI-H929-LUC 세포의 생육력을 특이적으로 검출할 수 있다. hu2F7-엑사테칸은 "혼합 세포 군"의 NCI-H929-LUC 세포를 유효하게 사멸시키고, 이는 B7-H4 양성 세포의 존재하에서, hu2F7-엑사테칸이 방관자 사멸 효과를 갖고, B7-H4 양성 세포를 사멸시킬 뿐만 아니라, 둔감한 B7-H4 음성 세포("단세포 군" 중의)도 사멸시킬 수 있음을 가리킨다.To study the effect of an antibody-drug conjugate conjugated to exatecan of the present invention on B7-H4 negative cell killing via the bystander effect, killing of the antibody-drug conjugate against a myeloma cell line with negative B7-H4 expression Activity was detected using the ONE-Glo™ Luciferase Assay Detection Kit. MX-1 cells were detected, centrifuged, counted, adjusted to a cell suspension of 7.5x10 6 cells/ml with complete medium, and plated onto white 96-well plates. 33 μl of the MX-1 cell suspension was added to each well of the “mixed cell group” and 33 μl PBS was added to each well of the “single cell group”. NCI-H929-LUC tumor cells with negative B7-H4 expression (Cobioer catalog number CBP30061L) were harvested. The cell density was adjusted to 1.5x10 6 cells/ml. 33 μl of NCI-H929-LUC cell suspension was added to each well of “mixed cell group” and “single cell group”. The cell plate was placed in an incubator at 37° C., 5% CO 2 and incubated overnight. On the second day of the experiment, the highest concentration of the antibody-drug conjugate hu2F7-exatecan (Compound 34, y=8) to be tested was uniformly adjusted to 3000 nM and diluted to obtain a 5-fold gradient of 9 doses. 33.3 μl of the diluted antibody-drug conjugate working solution was added to each well of the experimental plate and mixed gently. The cell plate was placed in an incubator at 37° C., 5% CO 2 and incubated for 48 hours. The cell culture plate was removed and equilibrated to room temperature. Then, 100 μl of ONE-Glo (trademark) luciferase reagent (Promega E6120) was added to each well. Cells were shaken and lysed for 10 minutes in the dark at room temperature. Cell lysates were centrifuged at 1000 rpm/min for 1 min and then transferred to a clear bottom 96-well plate at 180 μl per well. The plate was read at a wavelength of 490 nm on a microplate reader. Data were analyzed using Graphpad Prism software, and the experimental results are shown in Table 9. ONE-Glo (trademark) luciferase reagent can specifically detect the viability of NCI-H929-LUC cells. hu2F7-exatecan effectively kills NCI-H929-LUC cells of "mixed cell population", which indicates that in the presence of B7-H4-positive cells, hu2F7-exatecan has an bystander killing effect, and B7-H4-positive This indicates that not only does it kill cells, but it can also kill insensitive B7-H4 negative cells (in the "single cell population").
SEQUENCE LISTING <110> SHANGHAI HANSOH BIOMEDICAL CO., LTD. JIANGSU HANSOH PHARMACEUTICAL GROUP CO., LTD. <120> ANTI-B7-H4 ANTIBODY-DRUG CONJUGATE AND MEDICINAL USE THEREOF <130> 702041CPCT <140> PCT/CN2020/094856 <141> 2020-06-08 <150> CN 201910498993.2 <151> 2019-06-06 <150> CN 202010215322.3 <151> 2020-03-24 <160> 55 <170> SIPOSequenceListing 1.0 <210> 1 <211> 276 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <223> huB7-H4-His <400> 1 Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser Ile Ile Ser Ile Ile 1 5 10 15 Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly Ile Ser 20 25 30 Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala Gly Asn Ile 35 40 45 Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu 50 55 60 Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val Leu Gly Leu Val 65 70 75 80 His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu Gln Asp Glu Met 85 90 95 Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Ile Val Gly Asn 100 105 110 Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr 115 120 125 Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu 130 135 140 Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Val Asn Val Asp Tyr Asn 145 150 155 160 Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln 165 170 175 Pro Thr Val Val Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser 180 185 190 Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met 195 200 205 Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser 210 215 220 Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val 225 230 235 240 Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn Ser 245 250 255 Lys Ala Asp Tyr Lys Asp Asp Asp Asp Lys Gly Ser His His His His 260 265 270 His His His His 275 <210> 2 <211> 463 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <223> huB7-H4-Fc <400> 2 Phe Gly Ile Ser Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser 1 5 10 15 Ala Gly Asn Ile Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro 20 25 30 Asp Ile Lys Leu Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val 35 40 45 Leu Gly Leu Val His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu 50 55 60 Gln Asp Glu Met Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val 65 70 75 80 Ile Val Gly Asn Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp 85 90 95 Ala Gly Thr Tyr Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn 100 105 110 Ala Asn Leu Glu Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Val Asn 115 120 125 Val Asp Tyr Asn Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg 130 135 140 Trp Phe Pro Gln Pro Thr Val Val Trp Ala Ser Gln Val Asp Gln Gly 145 150 155 160 Ala Asn Phe Ser Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu 165 170 175 Asn Val Thr Met Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn 180 185 190 Asn Thr Tyr Ser Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly 195 200 205 Asp Ile Lys Val Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln 210 215 220 Leu Leu Asn Ser Lys Ala Gly Ser Gly Gly Gly Gly Asp Lys Thr His 225 230 235 240 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 245 250 255 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265 270 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 275 280 285 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 305 310 315 320 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 3 Gly Phe Thr Phe Ser Arg Tyr Gly Met Ser 1 5 10 <210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 4 Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val Lys 1 5 10 15 Gly <210> 5 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 5 Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr 1 5 <210> 6 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 6 His Ala Ser Gln Gly Ile Ser Ser Asn Ile Gly 1 5 10 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 7 His Gly Thr Asn Leu Glu Asp 1 5 <210> 8 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR3 <400> 8 Val Gln Tyr Ala Gln Phe Pro Tyr Thr 1 5 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 9 Gly Phe Thr Phe Ser Asn Tyr Tyr Met Ser 1 5 10 <210> 10 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 10 Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val Lys 1 5 10 15 Gly <210> 11 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 11 Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr 1 5 10 <210> 12 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 12 Arg Ala Ser Gln Ser Ile Ser Asp Tyr Leu His 1 5 10 <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 13 Phe Ala Ser Gln Ser Ile Ser 1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR3 <400> 14 Gln Asn Gly His Ser Phe Ser Leu Thr 1 5 <210> 15 <211> 118 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2G6 HCVR <400> 15 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 16 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2G6 LCVR <400> 16 Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys His Ala Ser Gln Gly Ile Ser Ser Asn 20 25 30 Ile Gly Trp Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile 35 40 45 Tyr His Gly Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 17 <211> 120 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F7 HCVR <400> 17 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 18 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F7 LCVR <400> 18 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile 35 40 45 Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Ser Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 19 <211> 448 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2G6 HC <400> 19 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 20 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2G6 LC <400> 20 Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys His Ala Ser Gln Gly Ile Ser Ser Asn 20 25 30 Ile Gly Trp Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile 35 40 45 Tyr His Gly Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 21 <211> 450 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F7 HC <400> 21 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 22 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F7 LC <400> 22 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile 35 40 45 Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Ser Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 23 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 23 Gly Tyr Thr Phe Thr Asn Ser Trp Met Asn 1 5 10 <210> 24 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 24 Gly Ile Tyr Pro Asn Ser Gly Asn Ile Glu Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 25 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 25 Asp Ser Arg Phe Ser Tyr 1 5 <210> 26 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 26 Lys Ala Ser Gln Asp Val Arg Thr Ala Val Ala 1 5 10 <210> 27 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 27 Ser Thr Ser Tyr Arg Tyr Thr 1 5 <210> 28 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR3 <400> 28 Gln Gln His Tyr Ser Thr Pro Leu Thr 1 5 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 29 Gly Asp Thr Phe Thr Thr Tyr 1 5 <210> 30 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 30 Tyr Leu Asn Ser Gly Ser 1 5 <210> 31 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 31 Asp Ser Arg Phe Ser Tyr 1 5 <210> 32 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 32 Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala 1 5 10 <210> 33 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 33 Ser Ala Ser Tyr Arg Tyr Thr 1 5 <210> 34 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR3 <400> 34 Gln Gln His Tyr Asn Thr Pro Leu Thr 1 5 <210> 35 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F8 HCVR <400> 35 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Pro Asn Arg Gly Asn Ile Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 36 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F8 LCVR <400> 36 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Thr Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 37 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu1C9 HCVR <400> 37 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Thr Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Leu Asn Arg Gly Ser Ser Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 38 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu1C9 LCVR <400> 38 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 39 <211> 445 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F8 HC <400> 39 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Pro Asn Arg Gly Asn Ile Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 40 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F8 LC <400> 40 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Thr Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 41 <211> 445 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu1C9HC <400> 41 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Thr Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Leu Asn Arg Gly Ser Ser Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 42 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu1C9 LC <400> 42 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 43 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Optimized HCDR1 <400> 43 Gly Tyr Thr Phe Thr Ser Ser Trp Met Asn 1 5 10 <210> 44 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Optimized HCDR2 <400> 44 Gly Ile Tyr Pro Asn Arg Gly Asn Ile Glu Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 45 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Optimized HCDR2 <400> 45 Tyr Leu Asn Arg Gly Ser 1 5 <210> 46 <211> 118 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2G6 HCVR <400> 46 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Ser Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 <210> 47 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2G6 LCVR <400> 47 Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly 1 5 10 15 Asp Thr Val Ser Ile Thr Cys His Ala Ser Gln Gly Ile Ser Ser Asn 20 25 30 Ile Gly Trp Leu Gln Gln Lys Pro Gly Lys Ser Phe Lys Ala Leu Ile 35 40 45 Tyr His Gly Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 48 <211> 120 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F7 HCVR <400> 48 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 49 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F7 LCVR <400> 49 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly 1 5 10 15 Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile 35 40 45 Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Ser Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 50 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F8 HCVR <400> 50 Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Ser 20 25 30 Trp Met Asn Trp Ala Lys Leu Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gly Ile Tyr Pro Asn Ser Gly Asn Ile Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Thr Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala 115 <210> 51 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F8 LCVR <400> 51 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Ser Ser Thr Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Ile Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 52 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 1C9 HCVR <400> 52 Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Thr Tyr 20 25 30 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gly Ile Tyr Leu Asn Ser Gly Ser Ser Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Ser Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala 115 <210> 53 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 1C9 LCVR <400> 53 Asp Ile Val Met Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile 35 40 45 Ser Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Gln Leu Glu Leu Lys 100 105 <210> 54 <211> 330 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> IgG1 C <400> 54 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 55 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Ig kappa C <400> 55 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 SEQUENCE LISTING <110> SHANGHAI HANSOH BIOMEDICAL CO., LTD. JIANGSU HANSOH PHARMACEUTICAL GROUP CO., LTD. <120> ANTI-B7-H4 ANTIBODY-DRUG CONJUGATE AND MEDICINAL USE THEREOF <130> 702041CPCT <140> PCT/CN2020/094856 <141> 2020-06-08 <150> CN 201910498993.2 <151> 2019-06-06 < 150> CN 202010215322.3 <151> 2020-03-24 <160> 55 <170> SIPOSequenceListing 1.0 <210> 1 <211> 276 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <223> huB7- H4-His <400> 1 Met Ala Ser Leu Gly Gin Ile Leu Phe Trp Ser Ile Ile Ser Ile Ile 1 5 10 15 Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly Ile Ser 20 25 30 Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala Gly Asn Ile 35 40 45 Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro Asp Ile Lys Leu 50 55 60 Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val Leu Gly Leu Val 65 70 75 80 His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu Gln Asp Glu Met 85 90 95 Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val Ile Val Gly Asn 100 105 110 Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp Ala Gly Thr Tyr 115 120 125 Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn Ala Asn Leu Glu 130 135 140 Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Val Asn Val Asp Tyr Asn 145 150 155 160 Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln 165 170 175 Pro Thr Val Val Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser 180 185 190 Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met 195 200 205 Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser 210 215 220 Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val 225 230 235 240 Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn Ser 245 250 255 Lys Ala Asp Tyr Lys Asp Asp Asp Asp Lys Gly Ser His His His His 260 265 270 His His His His 275 <210> 2 <211> 463 <212> PRT <213> Artificial Sequence <220> <221> PEPTIDE <223> huB7-H4-Fc <400> 2 Phe Gly Ile Ser Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser 1 5 10 15 Ala Gly Asn Ile Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro 20 25 30 Asp Ile Lys Leu Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly Val 35 40 45 Leu Gly Leu Val His Glu Phe Lys Glu Gly Lys Asp Glu Leu Ser Glu 50 55 60 Gln Asp Glu Met Phe Arg Gly Arg Thr Ala Val Phe Ala Asp Gln Val 65 70 75 80 Ile Val Gly Asn Ala Ser Leu Arg Leu Lys Asn Val Gln Leu Thr Asp 85 90 95 Ala Gly Thr Tyr Lys Cys Tyr Ile Ile Thr Ser Lys Gly Lys Gly Asn 100 105 110 Ala Asn Leu Glu Tyr Lys Thr Gly Ala Phe Ser Met Pro Glu Val Asn 115 120 125 Val Asp Tyr Asn Ala Ser Ser Glu Thr Leu Arg Cys Glu Ala Pro Arg 130 135 140 Trp Phe Pro Gln Pro Thr Val Val Trp Ala Ser Gln Val Asp Gln Gly 145 150 155 160 Ala Asn Phe Ser Glu Val Ser Asn Thr Ser Phe Glu Leu Asn Ser Glu 165 170 175 Asn Val Thr Met Lys Val Val Ser Val Leu Tyr Asn Val Thr Ile Asn 180 185 190 Asn Thr Tyr Ser Cys Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly 195 200 205 Asp Ile Lys Val Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln 210 215 220 Leu Leu Asn Ser Lys Ala Gly Ser Gly Gly Gly Gly Gly Asp Lys Thr His 225 230 235 240 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 245 250 255 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265 270 Pro Glu Val Thr Cys Val Val Val Val Asp Val Ser His Glu Asp Pro Glu 275 280 285 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 305 310 315 320 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN < 223> HCDR1 <400> 3 Gly Phe Thr Phe Ser Arg Tyr Gly Met Ser 1 5 10 <210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400 > 4 Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val Lys 1 5 10 15 Gly <210> 5 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 5 Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr 1 5 <210> 6 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 6 His Ala Ser Gln Gly Ile Ser Ser Asn Ile Gly 1 5 10 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 7 His Gly Thr Asn Leu Glu Asp 1 5 <210> 8 <211> 9 <212> PRT <213> Artificial Sequence <220> < 221> DOMAIN <223> LCDR3 <400> 8 Val Gln Tyr Ala Gln Phe Pro Tyr Thr 1 5 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 9 Gly Phe Thr Phe Ser Asn Tyr Tyr Met Ser 1 5 10 <210> 10 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 10 Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val Lys 1 5 10 15 Gly <210> 11 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400 > 11 Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr 1 5 10 <210> 12 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 12 Arg Ala Ser Gln Ser Ile Ser Asp Tyr Leu His 1 5 10 <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 13 Phe Ala Ser Gln Ser Ile Ser 1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR3 <400> 14 Gln Asn Gly His Ser Phe S er Leu Thr 1 5 <210> 15 <211> 118 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2G6 HCVR <400> 15 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 16 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2G6 LCVR <400> 16 Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys His Ala Ser Gln Gly Ile Ser Ser Asn 20 25 30 Ile Gly Trp Leu Gl n Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile 35 40 45 Tyr His Gly Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 17 <211> 120 <212> PRT <213 > Artificial Sequence <220> <221> DOMAIN <223> hu2F7 HCVR <400> 17 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 18 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F7 LCVR <400> 18 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile 35 40 45 Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Ser Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 19 <211> 448 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2G6 HC <400> 19 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu G lu Trp Val 35 40 45 Ser Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 20 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2G6 LC <400> 20 Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys His Ala Ser Gln Gly Ile Ser Ser Asn 20 25 30 Ile Gly Trp Leu Gln Gln Lys Pro Gly Lys AlaPro Lys Ala Leu Ile 35 40 45 Tyr His Gly Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 21 <211> 450 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F7 HC <400> 21 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 22 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F7 LC <400> 22 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile 35 40 45 Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Ser Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Se r 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 < 210> 23 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 23 Gly Tyr Thr Phe Thr Asn Ser Trp Met Asn 1 5 10 <210> 24 <211 > 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 24 Gly Ile Tyr Pro Asn Ser Gly Asn Ile Glu Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 25 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 25 Asp Ser Arg Phe Ser Tyr 1 5 <210> 26 <211> 11 <212> PRT < 213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 26 Lys Ala Ser Gln Asp Val Arg Thr Ala Val Ala 1 5 10 <210> 27 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <22 3> LCDR2 <400> 27 Ser Thr Ser Tyr Arg Tyr Thr 1 5 <210> 28 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR3 <400> 28 Gln Gln His Tyr Ser Thr Pro Leu Thr 1 5 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR1 <400> 29 Gly Asp Thr Phe Thr Thr Tyr 1 5 <210> 30 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR2 <400> 30 Tyr Leu Asn Ser Gly Ser 1 5 <210> 31 <211> 6 <212 > PRT <213> Artificial Sequence <220> <221> DOMAIN <223> HCDR3 <400> 31 Asp Ser Arg Phe Ser Tyr 1 5 <210> 32 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR1 <400> 32 Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala 1 5 10 <210> 33 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR2 <400> 33 Ser Ala Ser Tyr Arg Tyr Thr 1 5 <210> 34 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> LCDR 3 <400> 34 Gln Gln His Tyr Asn Thr Pro Leu Thr 1 5 <210> 35 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F8 HCVR <400> 35 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Pro Asn Arg Gly Asn Ile Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 36 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu2F8 LCVR <400> 36 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Thr Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 37 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu1C9 HCVR <400> 37 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Thr Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Leu Asn Arg Gly Ser Ser Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 38 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> hu1C9 LCVR <400> 38 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 39 <211> 445 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F8 HC <400> 39 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Pro Asn Arg Gly Asn Ile Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gin Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 20 5 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 40 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu2F8 LC <400> 40 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Thr Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 P he Asn Arg Gly Glu Cys 210 <210> 41 <211> 445 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu1C9HC <400> 41 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Thr Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Gly Ile Tyr Leu Asn Arg Gly Ser Ser Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 2 95 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 4 40 445 <210> 42 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> CHAIN <223> hu1C9 LC <400> 42 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 43 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Optimized HCDR1 <400> 43 Gly Tyr Thr Phe Thr Ser Ser Trp Met Asn 1 5 10 <210> 44 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Optimized HCDR2 <400> 44 Gly Ile Tyr Pro Asn Arg Gly Asn Ile Glu Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 45 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Optimized HCDR2 <400> 45 Tyr Leu Asn Arg Gly Ser 1 5 <210> 46 <211> 118 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2G6 HCVR <400> 46 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Gly Ile Asn Gly Gly Gly Ser Tyr Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Ser Gln Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 <210> 47 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2G6 LCVR <400> 47 Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly 1 5 10 15 Asp Thr Val Ser Ile Thr Cys His Ala Ser Gln Gly Ile Ser Ser Ser Asn 20 25 30 Ile Gly Trp Leu Gln Gln Lys Pro Gly Lys Ser Phe Lys Ala Leu Ile 35 40 45 Tyr His Gly Thr Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Ph e Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 48 <211> 120 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F7 HCVR <400 > 48 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Tyr Val Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Ser Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Glu Ser Tyr Ser Gln Gly Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 49 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F7 LCVR <400> 49 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly 1 5 10 15 Asp Arg V al Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile 35 40 45 Lys Phe Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Ser Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 50 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F8 HCVR <400> 50 Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Ser 20 25 30 Trp Met Asn Trp Ala Lys Leu Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gly Ile Tyr Pro Asn Ser Gly Asn Ile Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Thr Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala 115 <210> 51 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 2F8 LCVR <400> 51 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Ser Ser Thr Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Ile Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 52 <211> 115 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 1C9 HCVR <400> 52 Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Thr Tyr 20 25 30 Trp Met Asn Tr p Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gly Ile Tyr Leu Asn Ser Gly Ser Ser Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Ser Val Asp Thr Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Arg Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala 115 <210> 53 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> 1C9 LCVR <400> 53 Asp Ile Val Met Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile 35 40 45 Ser Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Gln Leu Glu Leu L ys 100 105 <210> 54 <211> 330 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> IgG1 C <400> 54 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 2 95 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 55 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> DOMAIN <223> Ig kappa C<400> 55 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105
Claims (41)
[화학식 A]
상기 식에서,
D는 세포독성 약물이고;
L1 및 L2는 링커 단위이고;
y는 1 내지 20의 수이고;
Ab는 항체 경쇄 가변 영역 및 항체 중쇄 가변 영역을 포함하는 B7-H4 항체 또는 이의 항원-결합 단편이고;
상기 항체 중쇄 가변 영역은 서열번호 3, 서열번호 4, 서열번호 5, 서열번호 9, 서열번호 10, 서열번호 11, 서열번호 23, 서열번호 24, 서열번호 25, 서열번호 29, 서열번호 30 및 서열번호 31로 이루어진 군으로부터 선택되는 서열에 제시된 하나 이상의 HCDR을 포함하고,
상기 항체 경쇄 가변 영역은 서열번호 6, 서열번호 7, 서열번호 8, 서열번호 12, 서열번호 13, 서열번호 14, 서열번호 26, 서열번호 27, 서열번호 28, 서열번호 32, 서열번호 33 및 서열번호 34로 이루어진 군으로부터 선택되는 서열에 제시된 하나 이상의 LCDR을 포함한다.An antibody-drug conjugate represented by the following formula (A) or a pharmaceutically acceptable salt or solvate thereof:
[Formula A]
In the above formula,
D is a cytotoxic drug;
L 1 and L 2 are linker units;
y is a number from 1 to 20;
Ab is a B7-H4 antibody or antigen-binding fragment thereof comprising an antibody light chain variable region and an antibody heavy chain variable region;
The antibody heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 30 and comprising at least one HCDR set forth in a sequence selected from the group consisting of SEQ ID NO: 31;
The antibody light chain variable region comprises SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 33 and one or more LCDRs set forth in a sequence selected from the group consisting of SEQ ID NO:34.
Ab의 항체 중쇄 가변 영역이 하기 (1) 내지 (4)로 이루어진 군으로부터 선택되는 어느 하나의 CDR을 포함하는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
(1) 서열번호 3에 제시된 HCDR1, 서열번호 4에 제시된 HCDR2 및 서열번호 5에 제시된 HCDR3;
(2) 서열번호 9에 제시된 HCDR1, 서열번호 10에 제시된 HCDR2 및 서열번호 11에 제시된 HCDR3;
(3) 서열번호 23에 제시된 HCDR1, 서열번호 24에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 및
(4) 서열번호 29에 제시된 HCDR1, 서열번호 30에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3.According to claim 1,
An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody heavy chain variable region of Ab comprises any one CDR selected from the group consisting of the following (1) to (4):
(1) HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 and HCDR3 shown in SEQ ID NO: 5;
(2) HCDR1 shown in SEQ ID NO: 9, HCDR2 shown in SEQ ID NO: 10 and HCDR3 shown in SEQ ID NO: 11;
(3) HCDR1 set forth in SEQ ID NO:23, HCDR2 set forth in SEQ ID NO:24 and HCDR3 set forth in SEQ ID NO:25; and
(4) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 30 and HCDR3 set forth in SEQ ID NO: 31.
Ab의 항체 경쇄 가변 영역이 하기 (1) 내지 (4)로 이루어진 군으로부터 선택되는 어느 하나의 CDR을 포함하는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
(1) 서열번호 6에 제시된 LCDR1, 서열번호 7에 제시된 LCDR2 및 서열번호 8에 제시된 LCDR3;
(2) 서열번호 12에 제시된 LCDR1, 서열번호 13에 제시된 LCDR2 및 서열번호 14에 제시된 LCDR3;
(3) 서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3; 및
(4) 서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3.According to claim 1,
An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody light chain variable region of Ab comprises any one CDR selected from the group consisting of the following (1) to (4):
(1) LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7 and LCDR3 shown in SEQ ID NO: 8;
(2) LCDR1 set forth in SEQ ID NO: 12, LCDR2 set forth in SEQ ID NO: 13 and LCDR3 set forth in SEQ ID NO: 14;
(3) LCDR1 set forth in SEQ ID NO:26, LCDR2 set forth in SEQ ID NO:27 and LCDR3 set forth in SEQ ID NO:28; and
(4) LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34.
Ab의 항체 중쇄 가변 영역 및 항체 경쇄 가변 영역이 하기 (1) 내지 (4)로 이루어진 군으로부터 선택되는 어느 하나의 CDR을 포함하는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
(1) 서열번호 3에 제시된 HCDR1, 서열번호 4에 제시된 HCDR2 및 서열번호 5에 제시된 HCDR3; 및
서열번호 6에 제시된 LCDR1, 서열번호 7에 제시된 LCDR2 및 서열번호 8에 제시된 LCDR3;
(2) 서열번호 9에 제시된 HCDR1, 서열번호 10에 제시된 HCDR2 및 서열번호 11에 제시된 HCDR3; 및
서열번호 12에 제시된 LCDR1, 서열번호 13에 제시된 LCDR2 및 서열번호 14에 제시된 LCDR3;
(3) 서열번호 23에 제시된 HCDR1, 서열번호 24에 제시된 HCDR2 및 서열번호 25에 제시된 HCDR3; 및
서열번호 26에 제시된 LCDR1, 서열번호 27에 제시된 LCDR2 및 서열번호 28에 제시된 LCDR3; 및
(4) 서열번호 29에 제시된 HCDR1, 서열번호 30에 제시된 HCDR2 및 서열번호 31에 제시된 HCDR3; 및
서열번호 32에 제시된 LCDR1, 서열번호 33에 제시된 LCDR2 및 서열번호 34에 제시된 LCDR3.According to claim 1,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody heavy chain variable region and the antibody light chain variable region of Ab comprise any one CDR selected from the group consisting of the following (1) to (4):
(1) HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 and HCDR3 shown in SEQ ID NO: 5; and
LCDR1 set forth in SEQ ID NO: 6, LCDR2 set forth in SEQ ID NO: 7 and LCDR3 set forth in SEQ ID NO: 8;
(2) HCDR1 shown in SEQ ID NO: 9, HCDR2 shown in SEQ ID NO: 10 and HCDR3 shown in SEQ ID NO: 11; and
LCDR1 shown in SEQ ID NO: 12, LCDR2 shown in SEQ ID NO: 13 and LCDR3 shown in SEQ ID NO: 14;
(3) HCDR1 set forth in SEQ ID NO:23, HCDR2 set forth in SEQ ID NO:24 and HCDR3 set forth in SEQ ID NO:25; and
LCDR1 shown in SEQ ID NO:26, LCDR2 shown in SEQ ID NO:27 and LCDR3 shown in SEQ ID NO:28; and
(4) HCDR1 set forth in SEQ ID NO: 29, HCDR2 set forth in SEQ ID NO: 30 and HCDR3 set forth in SEQ ID NO: 31; and
LCDR1 set forth in SEQ ID NO:32, LCDR2 set forth in SEQ ID NO:33 and LCDR3 set forth in SEQ ID NO:34.
Ab가 쥐 항체 또는 이의 단편, 키메라 항체 또는 이의 단편, 인간 항체 또는이의 단편, 또는 인간화된 항체 또는 이의 단편인 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.5. The method according to any one of claims 1 to 4,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is a murine antibody or fragment thereof, a chimeric antibody or fragment thereof, a human antibody or fragment thereof, or a humanized antibody or fragment thereof.
Ab가 하기 (a), (b) 및 (c) 중 어느 하나 또는 이들의 조합을 또한 포함하는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
(a) 인간 생식세포계열 경쇄 및 중쇄 서열 또는 이의 돌연변이 서열로부터 유래된 경쇄 프레임워크 영역 및 중쇄 프레임워크 영역;
(b) 인간 IgG1 또는 이의 변이체, IgG2 또는 이의 변이체, IgG3 또는 이의 변이체, 또는 IgG4 또는 이의 변이체로부터 유래된 중쇄 불변 영역, 바람직하게는 인간 IgG1, IgG2 또는 IgG4로부터 유래된 중쇄 불변 영역, 보다 바람직하게는 아미노산 돌연변이 후에 증대된 ADCC 독성을 갖는 IgG1의 중쇄 불변 영역, 가장 바람직하게는 서열번호 54에 제시된 중쇄 불변 영역; 및
(c) 인간 κ 쇄, λ 쇄 또는 이의 변이체로부터 유래된 경쇄 불변 영역, 바람직하게는 인간 κ 쇄로부터 유래된 경쇄 불변 영역, 보다 바람직하게는 서열번호 55에 제시된 경쇄 불변 영역.6. The method according to any one of claims 1 to 5,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein Ab also comprises any one of (a), (b) and (c) or a combination thereof:
(a) a light chain framework region and a heavy chain framework region derived from human germline light and heavy chain sequences or mutant sequences thereof;
(b) a heavy chain constant region derived from human IgG1 or variant thereof, IgG2 or variant thereof, IgG3 or variant thereof, or IgG4 or variant thereof, preferably a heavy chain constant region derived from human IgG1, IgG2 or IgG4, more preferably is a heavy chain constant region of IgG1 with enhanced ADCC toxicity after amino acid mutation, most preferably the heavy chain constant region set forth in SEQ ID NO: 54; and
(c) a light chain constant region derived from a human κ chain, a λ chain or a variant thereof, preferably a light chain constant region derived from a human κ chain, more preferably the light chain constant region set forth in SEQ ID NO:55.
Ab가 서열번호 16, 서열번호 18, 서열번호 36 또는 서열번호 38의 경쇄 가변 영역, 또는 서열번호 16, 서열번호 18, 서열번호 36 또는 서열번호 38과 적어도 70%, 75%, 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 경쇄 가변 영역을 포함하는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.7. The method according to any one of claims 1 to 6,
Ab is at least 70%, 75%, 80%, 85 with a light chain variable region of SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 36 or SEQ ID NO: 38, or SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 36 or SEQ ID NO: 38 An antibody-drug conjugate comprising a light chain variable region having %, 90%, 95% or 99% homology, or a pharmaceutically acceptable salt or solvate thereof.
Ab가 서열번호 15, 서열번호 17, 서열번호 35 또는 서열번호 37의 중쇄 가변 영역, 또는 서열번호 15, 서열번호 17, 서열번호 35 또는 서열번호 37과 적어도 70%, 75%, 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 중쇄 가변 영역을 포함하는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.8. The method according to any one of claims 1 to 7,
Ab is at least 70%, 75%, 80%, 85 with the heavy chain variable region of SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 35 or SEQ ID NO: 37, or SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 35 or SEQ ID NO: 37 An antibody-drug conjugate comprising a heavy chain variable region having %, 90%, 95% or 99% homology, or a pharmaceutically acceptable salt or solvate thereof.
Ab의 경쇄가 서열번호 20, 서열번호 22, 서열번호 40 또는 서열번호 42, 및 서열번호 20, 서열번호 22, 서열번호 40 또는 서열번호 42와 적어도 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 전장 경쇄로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.9. The method according to any one of claims 1 to 8,
The light chain of the Ab is at least 80%, 85%, 90%, 95% or An antibody-drug conjugate selected from the group consisting of a full-length light chain having 99% homology, or a pharmaceutically acceptable salt or solvate thereof.
Ab의 중쇄가 서열번호 19, 서열번호 21, 서열번호 39 또는 서열번호 41, 및 서열번호 19, 서열번호 21, 서열번호 39 또는 서열번호 41과 적어도 80%, 85%, 90%, 95% 또는 99%의 상동성을 갖는 전장 중쇄로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.10. The method according to any one of claims 1 to 9,
The heavy chain of the Ab is at least 80%, 85%, 90%, 95% or An antibody-drug conjugate selected from the group consisting of a full-length heavy chain having 99% homology, or a pharmaceutically acceptable salt or solvate thereof.
Ab의 중쇄 가변 영역 및 경쇄 가변 영역이 하기로 이루어진 군으로부터 선택되는 어느 하나인 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
(1) 서열번호 15에 제시된 중쇄 가변 영역 및 서열번호 16에 제시된 경쇄 가변 영역;
(2) 서열번호 17에 제시된 중쇄 가변 영역 및 서열번호 18에 제시된 경쇄 가변 영역;
(3) 서열번호 35에 제시된 중쇄 가변 영역 및 서열번호 36에 제시된 경쇄 가변 영역; 및
(4) 서열번호 37에 제시된 중쇄 가변 영역 및 서열번호 38에 제시된 경쇄 가변 영역.11. The method according to any one of claims 1 to 10,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the heavy and light chain variable regions of Ab are any one selected from the group consisting of:
(1) a heavy chain variable region set forth in SEQ ID NO: 15 and a light chain variable region set forth in SEQ ID NO: 16;
(2) a heavy chain variable region set forth in SEQ ID NO: 17 and a light chain variable region set forth in SEQ ID NO: 18;
(3) a heavy chain variable region set forth in SEQ ID NO: 35 and a light chain variable region set forth in SEQ ID NO: 36; and
(4) a heavy chain variable region set forth in SEQ ID NO: 37 and a light chain variable region set forth in SEQ ID NO: 38.
Ab가 하기로 이루어진 군으로부터 선택되는 어느 하나인 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
(1) 서열번호 20에 제시된 경쇄 및 서열번호 19에 제시된 중쇄;
(2) 서열번호 22에 제시된 경쇄 및 서열번호 21에 제시된 중쇄;
(3) 서열번호 40에 제시된 경쇄 및 서열번호 39에 제시된 중쇄; 및
(4) 서열번호 42에 제시된 경쇄 및 서열번호 41에 제시된 중쇄.12. The method of claim 11,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is any one selected from the group consisting of:
(1) a light chain set forth in SEQ ID NO: 20 and a heavy chain set forth in SEQ ID NO: 19;
(2) a light chain set forth in SEQ ID NO: 22 and a heavy chain set forth in SEQ ID NO: 21;
(3) a light chain set forth in SEQ ID NO:40 and a heavy chain set forth in SEQ ID NO:39; and
(4) a light chain set forth in SEQ ID NO: 42 and a heavy chain set forth in SEQ ID NO: 41.
항원-결합 단편이 Fab, Fab', F(ab')2, 단쇄 항체, 이량체화된 V 영역, 다이설파이드 결합 안정화된 V 영역, 및 CDR을 포함하는 펩타이드의 항원-결합 단편으로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.13. The method according to any one of claims 1 to 12,
the antigen-binding fragment is selected from the group consisting of an antigen-binding fragment of a peptide comprising Fab, Fab', F(ab') 2 , a single chain antibody, a dimerized V region, a disulfide bond stabilized V region, and a CDR An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof.
세포독성 약물이 독소, 화학요법제, 항생제, 방사성동위원소 및 핵산분해 효소로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.14. The method according to any one of claims 1 to 13,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the cytotoxic drug is selected from the group consisting of toxins, chemotherapeutic agents, antibiotics, radioisotopes and nucleases.
세포독성 약물이
튜불린 억제제 또는 세포 분열을 억제하는 DNA 국소이성화효소 억제제;
바람직하게는 DM1, DM3, DM4, SN-38, MMAF 및 MMAE;
보다 바람직하게는 튜불린 억제제 SN-38, MMAE 및 MMAF
로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.15. The method according to any one of claims 1 to 14,
cytotoxic drugs
tubulin inhibitors or DNA topoisomerase inhibitors that inhibit cell division;
preferably DM1, DM3, DM4, SN-38, MMAF and MMAE;
More preferably the tubulin inhibitors SN-38, MMAE and MMAF
An antibody-drug conjugate selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.
세포독성 약물이 캄토테신 유도체, 바람직하게는 엑사테칸(Exatecan)으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
15. The method according to any one of claims 1 to 14,
An antibody-drug conjugate wherein the cytotoxic drug is selected from camptothecin derivatives, preferably Exatecan, or a pharmaceutically acceptable salt or solvate thereof:
세포독성 약물이 하기로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
16. The method according to any one of claims 1 to 15,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the cytotoxic drug is selected from the group consisting of:
하기 화학식 I에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 I]
상기 식에서,
L1 및 L2는 링커 단위이고;
y는 1 내지 8로부터 선택되는 수, 바람직하게는 2 내지 4로부터 선택되는 수이고;
Ab는 제1항 내지 제12항 중 어느 한 항에 따른 B7-H4 항체 또는 이의 항원-결합 단편이다.According to claim 1,
An antibody-drug conjugate represented by Formula I, or a pharmaceutically acceptable salt or solvate thereof:
[Formula I]
In the above formula,
L 1 and L 2 are linker units;
y is a number selected from 1 to 8, preferably a number selected from 2 to 4;
Ab is the B7-H4 antibody or antigen-binding fragment thereof according to any one of claims 1 to 12.
하기 화학식 II에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 II]
상기 식에서,
L1 및 L2는 링커 단위이고;
y는 1 내지 8로부터 선택되는 수, 바람직하게는 2 내지 4로부터 선택되는 수이고;
Ab는 제1항 내지 제12항 중 어느 한 항에 따른 B7-H4 항체 또는 이의 항원-결합 단편이다.According to claim 1,
An antibody-drug conjugate represented by Formula II, or a pharmaceutically acceptable salt or solvate thereof:
[Formula II]
In the above formula,
L 1 and L 2 are linker units;
y is a number selected from 1 to 8, preferably a number selected from 2 to 4;
Ab is the B7-H4 antibody or antigen-binding fragment thereof according to any one of claims 1 to 12.
하기 화학식 III에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 III]
상기 식에서,
L1 및 L2는 링커 단위이고;
y는 1 내지 10으로부터 선택되는 수, 바람직하게는 2 내지 8로부터 선택되는 수, 보다 바람직하게는 4 내지 8의 수, 더욱 바람직하게는 6 내지 8의 수, 가장 바람직하게는 8이고;
Ab는 제1항 내지 제12항 중 어느 한 항에 따른 B7-H4 항체 또는 이의 항원-결합 단편이다.According to claim 1,
An antibody-drug conjugate represented by Formula III, or a pharmaceutically acceptable salt or solvate thereof:
[Formula III]
In the above formula,
L 1 and L 2 are linker units;
y is a number selected from 1 to 10, preferably a number selected from 2 to 8, more preferably a number from 4 to 8, even more preferably a number from 6 to 8, most preferably 8;
Ab is the B7-H4 antibody or antigen-binding fragment thereof according to any one of claims 1 to 12.
L1이 하기 화학식 B에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 B]
상기 식에서,
M1은 -CR1R2-이고;
R1 및 R2는 동일하거나 상이하고, 수소, 알킬, 할로겐, 하이드록실 및 아미노로 이루어진 군으로부터 독립적으로 선택되고;
n은 0 내지 5의 정수, 바람직하게는 1, 2 또는 3이다.21. The method according to any one of claims 18 to 20,
L 1 is an antibody-drug conjugate represented by Formula B: or a pharmaceutically acceptable salt or solvate thereof:
[Formula B]
In the above formula,
M 1 is —CR 1 R 2 —;
R 1 and R 2 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl and amino;
n is an integer from 0 to 5, preferably 1, 2 or 3.
L2가 하기 화학식 C에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 C]
상기 식에서,
M2는 -CR4R5-이고;
R3은 수소, 할로겐, 하이드록실, 아미노, 알킬, 알콕실 및 사이클로알킬로 이루어진 군으로부터 선택되고;
R4 및 R5는 동일하거나 상이하고, 수소, 알킬, 할로겐, 하이드록실 및 아미노로 이루어진 군으로부터 독립적으로 선택되고;
m은 0 내지 5의 정수, 바람직하게는 1, 2 또는 3이다.21. The method according to any one of claims 18 to 20,
L 2 is an antibody-drug conjugate represented by formula (C): or a pharmaceutically acceptable salt or solvate thereof:
[Formula C]
In the above formula,
M 2 is —CR 4 R 5 —;
R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, amino, alkyl, alkoxyl and cycloalkyl;
R 4 and R 5 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl and amino;
m is an integer from 0 to 5, preferably 1, 2 or 3.
L2가 하기 화학식 D에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 D]
-K1-K2-K3-K4-
상기 식에서,
K1은 이고, s는 2 내지 8의 정수이고;
K2는 -NR1(CH2CH2O)pCH2CH2C(O)-, -NR1(CH2CH2O)pCH2C(O)-, -S(CH2)pC(O)- 및 단일 결합으로 이루어진 군으로부터 선택되고, p는 1 내지 20, 바람직하게는 1 내지 6의 정수이고;
R1은 수소, 중수소, 하이드록실, 아미노, 알킬, 할로겐, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 선택되고;
K3은 테트라펩타이드 잔기이고, 바람직하게는 상기 테트라펩타이드 잔기는 페닐알라닌, 글리신, 발린, 리신, 시트룰린, 세린, 글루타메이트 및 아스파테이트 중 2개 이상으로 이루어진 군으로부터 선택되는 아미노산에 의해 형성된 펩타이드 잔기; 보다 바람직하게 테트라펩타이드 잔기 GGFG이고;
K4는 -NR2(CR3R4)t-이고, R2, R3 및 R4는 각각 독립적으로 수소, 중수소, 하이드록실, 아미노, 알킬, 할로겐, 할로알킬, 중수소화된 알킬 및 하이드록시알킬이고; t는 1 또는 2이다.21. The method according to any one of claims 18 to 20,
L 2 is an antibody-drug conjugate represented by formula (D): or a pharmaceutically acceptable salt or solvate thereof:
[Formula D]
-K 1 -K 2 -K 3 -K 4 -
In the above formula,
K 1 is and s is an integer from 2 to 8;
K 2 is -NR 1 (CH 2 CH 2 O) p CH 2 CH 2 C(O)-, -NR 1 (CH 2 CH 2 O) p CH 2 C(O)-, -S(CH 2 ) p selected from the group consisting of C(O)- and a single bond, p is an integer from 1 to 20, preferably from 1 to 6;
R 1 is selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, alkyl, halogen, haloalkyl, deuterated alkyl and hydroxyalkyl;
K 3 is a tetrapeptide residue, preferably the tetrapeptide residue is a peptide residue formed by an amino acid selected from the group consisting of at least two of phenylalanine, glycine, valine, lysine, citrulline, serine, glutamate and aspartate; more preferably the tetrapeptide residue GGFG;
K 4 is —NR 2 (CR 3 R 4 ) t —, and R 2 , R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, amino, alkyl, halogen, haloalkyl, deuterated alkyl and hydroxy hydroxyalkyl; t is 1 or 2.
링커 단위 -L2-의 K1 말단이 Ab에 연결되고, K4 말단이 L1에 연결되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.24. The method of claim 23,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the K 1 terminus of the linker unit -L 2 - is linked to Ab and the K 4 terminus is linked to L 1 .
L1이 -O-(CRaRb)m-CR5R6-C(O)-, -O-CR5R6-(CRaRb)m-, -O-CR5R6-, -NH-(CRaRb)m-CR5R6-C(O)- 및 -S-(CRaRb)m-CR5R6-C(O)-로 이루어진 군으로부터 선택되고;
Ra 및 Rb가 각각 독립적으로 수소, 중수소, 할로겐 및 알킬로 이루어진 군으로부터 선택되고;
R5가 할로알킬 또는 사이클로알킬이고,
R6이 수소, 할로알킬 및 사이클로알킬로 이루어진 군으로부터 선택되거나,
R5 및 R6 및 이들이 연결된 탄소 원자가 사이클로알킬을 형성하고;
m이 0, 1, 2, 3 또는 4인
항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.21. The method according to any one of claims 18 to 20,
L 1 is -O-(CR a R b ) m -CR 5 R 6 -C(O)-, -O-CR 5 R 6 -(CR a R b ) m -, -O-CR 5 R 6 - , -NH-(CR a R b ) m -CR 5 R 6 -C(O)- and -S-(CR a R b ) m -CR 5 R 6 -C(O)- and ;
R a and R b are each independently selected from the group consisting of hydrogen, deuterium, halogen and alkyl;
R 5 is haloalkyl or cycloalkyl,
R 6 is selected from the group consisting of hydrogen, haloalkyl and cycloalkyl,
R 5 and R 6 and the carbon atom to which they are connected form a cycloalkyl;
m is 0, 1, 2, 3 or 4
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof.
L1의 O 말단이 링커 단위 L2에 연결되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물.26. The method of claim 25,
An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the O terminus of L 1 is linked to a linker unit L 2 .
L1이 하기 화학식 E에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 E]
상기 식에서,
R5는 할로알킬 및 사이클로알킬로 이루어진 군으로부터 선택되고,
R6은 수소, 할로알킬 및 사이클로알킬로 이루어진 군으로부터 선택되거나,
R5 및 R6 및 이들이 연결된 탄소 원자는 사이클로알킬을 형성하고;
바람직하게는
R5는 C1-6 할로알킬 및 C3-6 사이클로알킬로 이루어진 군으로부터 선택되고,
R6은 수소, C1-6 할로알킬 및 C3-6 사이클로알킬로 이루어진 군으로부터 선택되거나,
R5 및 R6 및 이들이 연결된 탄소 원자는 C3-6 사이클로알킬을 형성하고;
m은 0 내지 4의 정수이고;
보다 바람직하게는, 화학식 E는 하기의 치환기로 이루어진 군으로부터 선택된다:
26. The method of claim 25,
L 1 is an antibody-drug conjugate represented by Formula E: or a pharmaceutically acceptable salt or solvate thereof:
[Formula E]
In the above formula,
R 5 is selected from the group consisting of haloalkyl and cycloalkyl,
R 6 is selected from the group consisting of hydrogen, haloalkyl and cycloalkyl,
R 5 and R 6 and the carbon atom to which they are connected form a cycloalkyl;
preferably
R 5 is selected from the group consisting of C 1-6 haloalkyl and C 3-6 cycloalkyl,
R 6 is selected from the group consisting of hydrogen, C 1-6 haloalkyl and C 3-6 cycloalkyl,
R 5 and R 6 and the carbon atom to which they are connected form a C 3-6 cycloalkyl;
m is an integer from 0 to 4;
More preferably, formula E is selected from the group consisting of the following substituents:
-L2-L1-이 하기의 구조에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
상기 식에서,
K2는 결합이고;
K3은 테트라펩타이드 잔기 GGFG이고;
R5는 할로알킬 및 C3-6 사이클로알킬로 이루어진 군으로부터 선택되고,
R6은 수소, 할로알킬 및 C3-6 사이클로알킬로 이루어진 군으로부터 선택되거나,
R5 및 R6 및 이들이 연결된 탄소 원자는 C3-6 사이클로알킬을 형성하고;
R2, R3 및 R4는 각각 독립적으로 수소 또는 알킬이고;
s는 2 내지 8의 정수이고;
m은 0 내지 4의 정수이고;
바람직하게는, 상기 -L2-L1-은 하기의 구조로 이루어진 군으로부터 선택된다:
.28. The method according to any one of claims 1 to 27,
-L 2 -L 1 -An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, as shown in the structure below:
In the above formula,
K 2 is a bond;
K 3 is the tetrapeptide residue GGFG;
R 5 is selected from the group consisting of haloalkyl and C 3-6 cycloalkyl,
R 6 is selected from the group consisting of hydrogen, haloalkyl and C 3-6 cycloalkyl,
R 5 and R 6 and the carbon atom to which they are connected form a C 3-6 cycloalkyl;
R 2 , R 3 and R 4 are each independently hydrogen or alkyl;
s is an integer from 2 to 8;
m is an integer from 0 to 4;
Preferably, said -L 2 -L 1 - is selected from the group consisting of:
.
하기 화학식 IV에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 IV]
상기 식에서,
W는 C1-8 알킬, C1-8 알킬-사이클로알킬 및 1 내지 8개의 원자의 선형 헤테로알킬로 이루어진 군으로부터 선택되고, 상기 헤테로알킬은 N, O 및 S로 이루어진 군으로부터 선택되는 1 내지 3개의 헤테로원자를 포함하고, 여기서 상기 C1-8 알킬, 사이클로알킬 및 선형 헤테로알킬은 할로겐, 하이드록실, 시아노, 아미노, 알킬, 클로로알킬, 중수소화된 알킬, 알콕실 및 사이클로알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기로 임의로 추가로 치환되고;
K2는 -NR1(CH2CH2O)p1CH2CH2C(O)-, -NR1(CH2CH2O)p1CH2C(O)-, -S(CH2)p1C(O)- 및 결합으로 이루어진 군으로부터 선택되고, R1은 수소 원자, 알킬, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 선택되고, p1은 1 내지 20의 정수이고;
K3은 2 내지 7개의 아미노산으로 이루어진 펩타이드 잔기이고, 상기 아미노산은 치환되거나 비치환될 수 있고; 치환되는 경우, 상기 치환기는 임의의 이용가능한 부착점에서 치환될 수 있고, 상기 치환기는 할로겐, 하이드록실, 시아노, 아미노, 알킬, 클로로알킬, 중수소화된 알킬, 알콕실 및 사이클로알킬로 이루어진 군으로부터 독립적으로 선택되는 하나 이상이고;
R2는 수소 원자, 알킬, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 독립적으로 선택되고;
R3 및 R4는 각각 독립적으로 수소 원자, 할로겐, 알킬, 할로알킬, 중수소화된 알킬 및 하이드록시알킬로 이루어진 군으로부터 선택되고;
R5는 할로겐, 할로알킬, 중수소화된 알킬, 사이클로알킬, 헤테로사이클릴, 아릴 및 헤테로아릴로 이루어진 군으로부터 선택되고,
R6은 수소 원자, 할로겐, 할로알킬, 중수소화된 알킬, 사이클로알킬, 헤테로사이클릴, 아릴 및 헤테로아릴로 이루어진 군으로부터 선택되거나,
R5 및 R6 및 이들이 연결된 탄소 원자는 사이클로알킬 또는 헤테로사이클릴을 형성하고;
m은 0 내지 4의 정수이고;
y는 1 내지 10이고, y는 소수 또는 정수이고;
Ab는 항-B7-H4 항체 또는 이의 항원-결합 단편이다.13. The method according to any one of claims 1 to 12,
An antibody-drug conjugate represented by Formula IV, or a pharmaceutically acceptable salt or solvate thereof:
[Formula IV]
In the above formula,
W is selected from the group consisting of C 1-8 alkyl, C 1-8 alkyl-cycloalkyl and linear heteroalkyl of 1 to 8 atoms, wherein the heteroalkyl is 1 to selected from the group consisting of N, O and S contains 3 heteroatoms, wherein said C 1-8 alkyl, cycloalkyl and linear heteroalkyl consist of halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxyl and cycloalkyl. optionally further substituted with one or more substituents selected from the group;
K 2 is -NR 1 (CH 2 CH 2 O) p1 CH 2 CH 2 C(O)-, -NR 1 (CH 2 CH 2 O) p1 CH 2 C(O)-, -S(CH 2 ) p1 C(O)— and a bond, R 1 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl, p 1 is an integer from 1 to 20;
K 3 is a peptide residue consisting of 2 to 7 amino acids, which amino acids may be substituted or unsubstituted; When substituted, said substituent may be substituted at any available point of attachment, said substituent being from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxyl and cycloalkyl. at least one independently selected from;
R 2 is independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl;
R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, deuterated alkyl and hydroxyalkyl;
R 5 is selected from the group consisting of halogen, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 6 is selected from the group consisting of a hydrogen atom, halogen, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5 and R 6 and the carbon atom to which they are connected form a cycloalkyl or heterocyclyl;
m is an integer from 0 to 4;
y is 1 to 10, y is a decimal or an integer;
Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof.
하기 화학식 I-A에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 I-A]
.19. The method of claim 18,
An antibody-drug conjugate represented by Formula IA, or a pharmaceutically acceptable salt or solvate thereof:
[Formula IA]
.
하기 화학식 I-B에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 I-B]
.19. The method of claim 18,
An antibody-drug conjugate represented by Formula IB, or a pharmaceutically acceptable salt or solvate thereof:
[Formula IB]
.
하기 화학식 II-A에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 II-A]
.20. The method of claim 19,
An antibody-drug conjugate represented by Formula II-A, or a pharmaceutically acceptable salt or solvate thereof:
[Formula II-A]
.
하기 화학식 II-B에 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
[화학식 II-B]
.20. The method of claim 19,
An antibody-drug conjugate represented by Formula II-B, or a pharmaceutically acceptable salt or solvate thereof:
[Formula II-B]
.
하기 화학식 IV-A에 제시되고:
[화학식 IV-A]
,
바람직하게는, 하기와 같이 제시된 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
.30. The method of claim 29,
It is presented in Formula IV-A below:
[Formula IV-A]
,
Preferably, an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as shown below:
.
하기의 화합물로 이루어진 군으로부터 선택되는 항체-약물 접합체 또는 이의 약학적으로 허용가능한 염 또는 용매화물:
상기 식에서,
y는 2 내지 10, 바람직하게는 4 내지 8, 보다 바람직하게는 6 내지 8, 더욱 바람직하게는 7 내지 8로부터 선택되고, 가장 바람직하게는 8이다.35. The method of any one of claims 1 to 34,
An antibody-drug conjugate selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
In the above formula,
y is selected from 2 to 10, preferably 4 to 8, more preferably 6 to 8, still more preferably 7 to 8, and most preferably 8.
상기 식에서,
Ab는 항-B7-H4 항체 또는 이의 항원-결합 단편이고;
W, K2, K3, R2 내지 R6, m 및 y는 제29항에 정의된 바와 같다.A method for preparing an antibody-drug conjugate shown in Formula IV or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: performing a coupling reaction with a compound shown in Formula F when Ab is reduced to obtain the formula Methods of preparing the compounds set forth in IV:
In the above formula,
Ab is an anti-B7-H4 antibody or antigen-binding fragment thereof;
W, K 2 , K 3 , R 2 to R 6 , m and y are as defined in claim 29 .
화학식 F에 제시된 화합물이 하기 화학식 F-1에 제시된 화합물 또는 이의 호변이성질체, 메소머, 라세메이트, 거울상이성질체, 부분입체이성질체 또는 이들의 혼합 형태, 또는 이들의 약학적으로 허용가능한 염인, 제조 방법:
[화학식 F-1]
상기 식에서,
K2, K3, R2 내지 R6, s 및 m은 제28항에 정의된 바와 같다.37. The method of claim 36,
A method for preparing the compound represented by Formula F, wherein the compound represented by Formula F-1 below, or a tautomer, mesomemer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
[Formula F-1]
In the above formula,
K 2 , K 3 , R 2 to R 6 , s and m are as defined in claim 28 .
.A compound represented by Formula F or Formula F-1 selected from the group consisting of:
.
높은 B7-H4 발현을 갖는 암의 치료를 위한 약제의 제조를 위한 용도로서, 상기 암이 인간 뇌의 성상모세포종, 인간 인두암, 부신 종양, AIDS-관련 암, 폐포 연부 육종, 성상세포종, 방광암, 골암, 뇌 및 척수암, 전이성 뇌종양, 유방암, 경동맥체종양, 자궁경부암, 연골육종, 척색종, 신장의 발색세포암종(chromophore cell carcinoma), 투명세포암종, 결장암, 결장직장암, 결합조직 증식성 소원형세포종양, 뇌실막종, 유잉육종, 골외점액 연골육종, 골성 불완전 섬유원증, 골의 섬유성 이형성증, 담낭 또는 담관암종, 위암, 임신성 융모성 질환, 생식 세포 종양, 두경부암, 간세포 암종, 섬 세포 종양, 카포시 육종, 신장암, 백혈병, 지방육종/악성 지방종 종양, 간암, 림프종, 폐암, 수모세포종, 흑색종, 수막종, 다발성 내분비종양, 다발성 골수종, 골수이형성 증후군, 신경모세포종, 신경내분비종양, 난소암, 췌장암, 갑상선 유두암, 부갑상선 선종, 소아암, 말초신경초종, 갈색세포종(pheocytoma), 뇌하수체종양, 전립선암, 후포도막흑색종, 신장전이암, 횡문근종양, 횡문근육종, 육종, 피부암, 연조직 육종, 편평 세포 암종, 활액 육종, 고환암, 흉선암, 갑상선 전이암 및 자궁암으로 이루어진 군으로부터 선택되는, 용도.41. The method of claim 40,
Use for the manufacture of a medicament for the treatment of a cancer having high B7-H4 expression, wherein the cancer is astroblastoma of the human brain, human pharyngeal cancer, adrenal tumor, AIDS-related cancer, alveolar soft sarcoma, astrocytoma, bladder cancer, Bone cancer, brain and spinal cord cancer, metastatic brain tumor, breast cancer, carotid body tumor, cervical cancer, chondrosarcoma, chordoma, chromophore cell carcinoma of the kidney, clear cell carcinoma, colon cancer, colorectal cancer, connective tissue proliferative bovine Atopic cell tumor, ependymoma, Ewing's sarcoma, extraosseous mucinous chondrosarcoma, osseous incomplete fibrosis, fibrous dysplasia of bone, gallbladder or cholangiocarcinoma, gastric cancer, gestational villous disease, germ cell tumor, head and neck cancer, hepatocellular carcinoma, islet cell Tumor, Kaposi's sarcoma, renal cancer, leukemia, liposarcoma/malignant lipoma tumor, liver cancer, lymphoma, lung cancer, medulloblastoma, melanoma, meningioma, multiple endocrine tumor, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumor, ovary Cancer, pancreatic cancer, papillary thyroid cancer, parathyroid adenoma, childhood cancer, peripheral schwannoma, pheocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, renal metastasis, rhabdomyosarcoma, rhabdomyosarcoma, sarcoma, skin cancer, soft tissue sarcoma, squamous A use selected from the group consisting of cell carcinoma, synovial sarcoma, testicular cancer, thymus cancer, thyroid metastasis and uterine cancer.
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